Compositions and methods for improved delivery of lipid regulating agents

ABSTRACT

The present invention relates to triglyceride-free pharmaceutical compositions for delivery of hydrophobic therapeutic agents. Compositions of the present invention include a hydrophobic therapeutic agent and a carrier, where the carrier is formed from a combination of a hydrophilic surfactant and a hydrophobic surfactant. Upon dilution with an aqueous solvent, the composition forms a clear, aqueous dispersion of the surfactants containing the therapeutic agent. The invention also provides methods of treatment with hydrophobic therapeutic agents using these compositions.

FIELD OF THE INVENTION

[0001] The present invention relates to drug delivery systems, and inparticular to pharmaceutical compositions for the improved delivery ofhydrophobic compounds.

BACKGROUND

[0002] Hydrophobic therapeutic agents, i.e., therapeutic compoundshaving poor solubility in aqueous solution, present difficult problemsin formulating such compounds for effective administration to patients.A well-designed formulation must, at a minimum, be capable of presentinga therapeutically effective amount of the hydrophobic compound to thedesired absorption site, in an absorbable form. Even this minimalfunctionality is difficult to achieve when delivery of the hydrophobictherapeutic agent requires interaction with aqueous physiologicalenvironments, such as gastric fluids and intestinal fluids.Pharmaceutical compositions for delivery of such hydrophobic therapeuticagents must carry the hydrophobic compound through the aqueousenvironment, while maintaining the hydrophobic compound in an absorbableform, and avoiding the use of physiologically harmful solvents orexcipients.

[0003] A number of approaches to formulating hydrophobic therapeuticagents for oral or parenteral delivery are known. One well-knownapproach uses surfactant micelles to solubilize and transport thetherapeutic agent. Micelles are agglomerates of colloidal dimensionsformed by amphiphilic compounds under certain conditions. Micelles, andpharmaceutical compositions containing micelles, have been extensivelystudied and are described in detail in the literature; see, e.g.,Remington's Pharmaceutical Sciences, 17^(th) ed. (1985), the disclosureof which is incorporated herein in its entirety. In aqueous solution,micelles can incorporate hydrophobic therapeutic agents in thehydrocarbon core of the micelle, or entangled at various positionswithin the micelle walls. Although micellar formulations can solubilizea variety of hydrophobic therapeutic agents, the loading capacity ofconventional micelle formulations is limited by the solubility of thetherapeutic agent in the micelle surfactant. For many hydrophobictherapeutic agents, such solubility is too low to offer formulationsthat can deliver therapeutically effective doses.

[0004] Another conventional approach takes advantage of the increasedsolubility of hydrophobic therapeutic agents in oils (triglycerides).Hydrophobic therapeutic agents, while poorly soluble in aqueoussolution, could be sufficiently lipophilic that therapeuticallyeffective concentrations of the therapeutic agents can be prepared intriglyceride-based solvents. Thus, one conventional approach is tosolubilize a hydrophobic therapeutic agent in a bioacceptabletriglyceride solvent, such as a digestible vegetable oil, and dispersethis oil phase in an aqueous solution. The dispersion may be stabilizedby emulsifying agents and provided in emulsion form. Alternatively, thetherapeutic agent can be provided in a water-free formulation, with anaqueous dispersion being formed in the in vivo gastrointestinalenvironment. The properties of these oil-based formulations aredetermined by such factors as the size of the triglyceride/therapeuticagent colloidal particles and the presence or absence of surfactantadditives.

[0005] In simplest form, a triglyceride-containing formulation suitablefor delivering hydrophobic therapeutic agents through an aqueousenvironment is an oil-in-water emulsion. Such emulsions contain thehydrophobic therapeutic agent solubilized in an oil phase which isdispersed in an aqueous environment with the aid of a surfactant. Thesurfactant may be present in the oil-based formulation itself, or may bea compound provided in the gastrointestinal system, such as bile salts,which are known to be in vivo emulsifying agents. The colloidal oilparticles sizes are relatively large, ranging from several hundrednanometers to several microns in diameter, in a broad particle sizedistribution. Since the particle sizes are on the order of or greaterthan the wavelength range of visible light, such emulsions, whenprepared in an emulsion dosage form, are visibly “cloudy” or “milky” tothe naked eye.

[0006] Although triglyceride-based pharmaceutical compositions areuseful in solubilizing and delivering some hydrophobic therapeuticagents, such compositions are subject to a number of significantlimitations and disadvantages. Emulsions are thermodynamically unstable,and colloidal emulsion particles will spontaneously agglomerate,eventually leading to complete phase separation. The tendency toagglomerate and phase separate presents problems of storage andhandling, and increases the likelihood that pharmaceutical emulsionsinitially properly prepared will be in a less optimal, less effective,and poorly-characterized state upon ultimate administration to apatient. Uncharacterized degradation is particularly disadvantageous,since increased particle size slows the rate of transport of thecolloidal particle and digestion of the oil component, and hence therate and extent of absorption of the therapeutic agent. These problemslead to poorly-characterized and potentially harmful changes in theeffective dosage received by the patient. Moreover, changes in colloidalemulsion particle size are also believed to render absorption moresensitive to and dependent upon conditions in the gastrointestinaltract, such as pH, enzyme activity, bile components, and stomachcontents. Such uncertainty in the rate and extent of ultimate absorptionof the therapeutic agent severely compromises the medical professional'sability to safely administer therapeutically effective dosages.

[0007] A further disadvantage of triglyceride-containing compositions isthe dependence of therapeutic agent absorption on the rate and extent oflipolysis. Although colloidal emulsion particles can transporthydrophobic therapeutic agents through the aqueous environment of thegastrointestinal tract, ultimately the triglyceride must be digested andthe therapeutic agent must be released in order to be absorbed throughthe intestinal mucosa. The triglyceride carrier is emulsified by bilesalts and hydrolyzed, primarily by pancreatic lipase. The rate andextent of lipolysis, however, are dependent upon several factors thatare difficult to adequately control. For example, the amount and rate ofbile salt secretion affect the lipolysis of the triglycerides, and thebile salt secretion can vary with stomach contents, with metabolicabnormalities, and with functional changes of the liver, bile ducts,gall bladder and intestine. Lipase availability in patients withdecreased pancreatic secretory function, such as cystic fibrosis orchronic pancreatitis, may be undesirably low, resulting in a slow andincomplete triglyceride lipolysis. The activity of lipase is pHdependent, with deactivation occurring at about pH 3, so that thelipolysis rate will vary with stomach contents, and may be insufficientin patients with gastric acid hyper-secretion. Moreover, certainsurfactants commonly used in the preparation of pharmaceuticalemulsions, such as polyethoxylated castor oils, may themselves act asinhibitors of lipolysis. Although recent work suggests that certainsurfactant combinations, when used in combination with digestible oilsin emulsion preparations, can substantially decrease thelipolysis-inhibiting effect of some common pharmaceutical surfactants(see, U.S. Pat. No. 5,645,856), such formulations are still subject tothe other disadvantages of pharmaceutical emulsions andtriglyceride-based formulations.

[0008] Yet another approach is based on formation of “microemulsions.”Like an emulsion, a microemulsion is a liquid dispersion of oil inwater, stabilized by surfactants. The microemulsion particles aresmaller than those of an emulsion, rendering the microemulsionessentially optically clear. Microemulsions, however, arethermodynamically stable, and are not subject to the particleagglomeration problems of conventional emulsions. It is generallybelieved that microemulsions are micelle-like particles, having anessentially micellar structure but containing a distinct oil phase inthe micelle “core”. These micelle-like particles are often referred toas “swollen micelles”, a term which emphasizes their close relationshipto true micellar particles. Despite their close relationship tomicelles, microemulsions function quite differently in drug deliverysystems. The majority of hydrophobic therapeutic agents are lipophilic,and have greater solubility in triglycerides than in surfactants. As aresult, the hydrophobic therapeutic agent in a microemulsion-baseddelivery system is preferentially solvated in the triglyceride phase,which is in turn encapsulated in the swollen micelle. The preferentialpartitioning in the triglyceride phase results in higher loadingcapacities than in comparable micelle-based systems, but at the cost ofintroducing into the delivery system the lipolysis-dependence and otherdisadvantages associated with the presence of triglycerides. Inaddition, the larger size of microemulsion particles, relative to truemicelles, results in a slower rate of particle diffusion, and thus aslower rate of therapeutic agent absorption.

[0009] Thus, there is a need for pharmaceutical compositions thatovercome the limitations of conventional micelle formulations, butwithout suffering from the disadvantages of triglyceride-containingformulations.

SUMMARY OF THE INVENTION

[0010] It is therefore an object of the present invention to providepharmaceutical compositions capable of solubilizing therapeuticallyeffective amounts of hydrophobic therapeutic agents.

[0011] It is another object of the invention to provide pharmaceuticalcompositions that are homogeneous and thermodynamically stable.

[0012] It is yet another object of the invention to providepharmaceutical compositions having a small and narrow particle sizedistribution.

[0013] It is still another object of the invention to providepharmaceutical compositions of a hydrophobic therapeutic agent that arenot dependent upon lipolysis for bioabsorption.

[0014] It is still another object of the invention to provide methods oftreating a patient with a hydrophobic therapeutic agent.

[0015] It is still another object of the invention to provide lessgreasy pharmaceutical compositions for topical/transdermal delivery.

[0016] In accordance with these and other objects and features, thepresent invention provides pharmaceutical compositions for improveddelivery of hydrophobic therapeutic agents. In one embodiment, thepresent invention provides a triglyceride-free pharmaceuticalcomposition including a hydrophobic therapeutic agent and a carrier. Thecarrier includes a hydrophilic surfactant and a hydrophobic surfactantin amounts such that upon dilution with an aqueous solution such assimulated gastrointestinal fluids the carrier forms a clear aqueousdispersion of the hydrophilic and hydrophobic surfactants containing thehydrophobic therapeutic agent.

[0017] In another embodiment, the present invention provides a clearaqueous dispersion containing a hydrophilic surfactant, a hydrophobicsurfactant and a hydrophobic therapeutic agent. The dispersion issubstantially free of triglycerides.

[0018] In another embodiment, the present invention relates to atriglyceride-free pharmaceutical composition which includes ahydrophilic surfactant and a hydrophobic surfactant in amounts such thatupon dilution with an aqueous solution a clear aqueous dispersion isformed, a first amount of a hydrophobic therapeutic agent solubilized inthe clear aqueous dispersion, and a second amount of the hydrophobictherapeutic agent that remains non-solubilized but dispersed.

[0019] In another embodiment, the present invention relates to methodsof increasing the rate and/or extent of absorption of hydrophobictherapeutic agents by administering to a patient a pharmaceuticalcomposition of the present invention.

[0020] These and other objects and features of the present inventionwill become more fully apparent from the following description andappended claims, or may be learned by the practice of the invention asset forth hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to illustrate the manner in which the above-recited andother advantages and objects of the invention are obtained, a moreparticular description of the invention briefly described above will berendered by reference to the specific embodiments shown in the appendeddrawings. Understanding that these drawings depict only typicalembodiments of the invention and are not therefore limiting of itsscope, the invention will be described and explained with additionalspecificity and detail through the use of the accompanying drawing, inwhich:

[0022]FIG. 1 shows the enhanced bioabsorption of a hydrophobictherapeutic agent in the compositions of the present invention, relativeto a commercial formulation.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention overcomes the problems described abovecharacteristic of conventional formulations such as micelleformulations, emulsions, and microemulsions, by providing uniquetriglyceride-free pharmaceutical compositions. Surprisingly, the presentinventors have found that compositions including a combination of ahydrophilic surfactant and a hydrophobic surfactant can solubilizetherapeutically effective amounts of hydrophobic therapeutic agentswithout recourse to the use of triglycerides, thereby avoiding thelipolysis dependence and other disadvantages of conventionalformulations. Use of these formulations results in an enhanced rateand/or extent of absorption of the hydrophobic therapeutic agent.

[0024] A. Pharmaceutical Compositions

[0025] In one embodiment, the present invention provides apharmaceutical composition including a carrier and a hydrophobictherapeutic agent. The carrier includes a hydrophilic surfactant and ahydrophobic surfactant in amounts such that upon dilution with anaqueous solution the carrier forms a clear aqueous dispersion of thehydrophilic and hydrophobic surfactants containing the hydrophobictherapeutic agent. It is a particular feature of the present inventionthat the carrier is substantially free of triglycerides, therebyproviding surprising and important advantages over conventional,triglyceride-containing formulations.

[0026] 1. Surfactants

[0027] The carrier includes at least one hydrophilic surfactant and atleast one hydrophobic surfactant. As is well known in the art, the terms“hydrophilic” and “hydrophobic” are relative terms. To function as asurfactant, a compound must necessarily include polar or chargedhydrophilic moieties as well as non-polar hydrophobic (lipophilic)moieties; i.e., a surfactant compound must be amphiphilic. An empiricalparameter commonly used to characterize the relative hydrophilicity andhydrophobicity of non-ionic amphiphilic compounds is thehydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLBvalues are more hydrophobic, and have greater solubility in oils, whilesurfactants with higher HLB values are more hydrophilic, and havegreater solubility in aqueous solutions.

[0028] Using HLB values as a rough guide, hydrophilic surfactants aregenerally considered to be those compounds having an HLB value greaterthan about 10, as well as anionic, cationic, or zwitterionic compoundsfor which the HLB scale is not generally applicable. Similarly,hydrophobic surfactants are compounds having an HLB value less thanabout 10.

[0029] It should be appreciated that the HLB value of a surfactant ismerely a rough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions. For many important surfactants,including several polyethoxylated surfactants, it has been reported thatHLB values can differ by as much as about 8 HLB units, depending uponthe empirical method chosen to determine the HLB value (Schott, J.Pharm. Sciences, 79(1), 87-88 (1990)). Likewise, for certainpolypropylene oxide containing block copolymers (PLURONIC® surfactants,BASF Corp.), the HLB values may not accurately reflect the true physicalchemical nature of the compounds. Finally, commercial surfactantproducts are generally not pure compounds, but are complex mixtures ofcompounds, and the HLB value reported for a particular compound may moreaccurately be characteristic of the commercial product of which thecompound is a major component. Different commercial products having thesame primary surfactant component can, and typically do, have differentHLB values. In addition, a certain amount of lot-to-lot variability isexpected even for a single commercial surfactant product. Keeping theseinherent difficulties in mind, and using HLB values as a guide, oneskilled in the art can readily identify surfactants having suitablehydrophilicity or hydrophobicity for use in the present invention, asdescribed herein.

[0030] The hydrophilic surfactant can be any hydrophilic surfactantsuitable for use in pharmaceutical compositions. Such surfactants can beanionic, cationic, zwitterionic or non-ionic, although non-ionichydrophilic surfactants are presently preferred. As discussed above,these non-ionic hydrophilic surfactants will generally have HLB valuesgreater than about 10. Mixtures of hydrophilic surfactants are alsowithin the scope of the invention.

[0031] Similarly, the hydrophobic surfactant can be any hydrophobicsurfactant suitable for use in pharmaceutical compositions. In general,suitable hydrophobic surfactants will have an HLB value less than about10. Mixtures of hydrophobic surfactants are also within the scope of theinvention.

[0032] The choice of specific hydrophobic and hydrophilic surfactantsshould be made keeping in mind the particular hydrophobic therapeuticagent to be used in the composition, and the range of polarityappropriate for the chosen therapeutic agent, as discussed in moredetail below. With these general principles in mind, a very broad rangeof surfactants is suitable for use in the present invention. Suchsurfactants can be grouped into the following general chemical classesdetailed in the Tables below. The HLB values given in the Tables belowgenerally represent the HLB value as reported by the manufacturer of thecorresponding commercial product. In cases where more than onecommercial product is listed, the HLB value in the Tables is the valueas reported for one of the commercial products, a rough average of thereported values, or a value that, in the judgment of the presentinventors, is more reliable. It should be emphasized that the inventionis not limited to the surfactants in the following Tables, which showrepresentative, but not exclusive, lists of available surfactants.

[0033] 1.1. Polyethoxylated Fatty Acids

[0034] Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Among the PEG-fatty acid monoesters, esters of lauric acid,oleic acid, and stearic acid are most useful. Among the surfactants ofTable 1, preferred hydrophilic surfactants include PEG-8 laurate, PEG-8oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate,PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20oleate. Examples of polyethoxylated fatty acid monoester surfactantscommercially available are shown in Table 1. TABLE 1 PEG-Fatty AcidMonoester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB PEG4-100 monolaurate Crodet L series (Croda) >9 PEG 4-100 monooleate CrodetO series (Croda) >8 PEG 4-100 monostearate Crodet S series (Croda), MyrjSeries >6 (Atlas/ICI) PEG 400 distearate Cithrol 4DS series (Croda) >10PEG 100,200,300 Cithrol ML series (Croda) >10 monolaurate PEG100,200,300 Cithrol MO series (Croda) >10 monooleate PEG 400 dioleateCithrol 4DO series (Croda) >10 PEG 400-1000 Cithrol MS series(Croda) >10 monostearate PEG-1 stearate Nikkol MYS-1EX (Nikko), Coster 2K1 (Condea) PEG-2 stearate Nikkol MYS-2 (Nikko) 4 PEG-2 oleate NikkolMYO-2 (Nikko) 4.5 PEG-4 laurate Mapeg ® 200 ML (PPG), Kessco ® 9.3 PEG200ML (Stepan), LIPOPEG 2L (LIPO Chem.) PEG-4 oleate Mapeg ® 200 MO(PPG), Kessco ® 8.3 PEG200 MO (Stepan), PEG-4 stearate Kessco ® PEG 200MS (Stepan), 6.5 Hodag 20 S (Calgene), Nikkol MYS-4 (Nikko) PEG-5stearate Nikkol TMGS-5 (Nikko) 9.5 PEG-5 oleate Nikkol TMGO-5 (Nikko)9.5 PEG-6 oleate Algon OL 60 (Auschem SpA), Kessco ® PEG 300 MO(Stepan), 8.5 Nikkol MYO-6 (Nikko), Emulgante A6 (Condea) PEG-7 oleateAlgon OL 70 (Auschem SpA) 10.4 PEG-6 laurate Kessco ® PEG300 ML (Stepan)11.4 PEG-7 laurate Lauridac 7 (Condea) 13 PEG-6 stearate Kessco ® PEG300MS (Stepan) 9.7 PEG-8 laurate Mapeg ® 400 ML (PPG), LIPOPEG 13 4DL(LipoChem.) PEG-8 oleate Mapeg ® 400 MO (PPG), Emulgante 12 A8 (Condea) PEG-8stearate Mapeg ® 400 MS (PPG), Myrj 45 12 PEG-9 oleate Emulgante A9(Condea) >10 PEG-9 stearate Cremophor S9 (BASF) >10 PEG-10 laurateNikkol MYL-10 (Nikko), Lauridac 10 13 (Croda) PEG-10 oleate NikkolMYG-10 (Nikko) 11 PEG-10 stearate Nikkol MYS-10 (Nikko), Coster K100 11(Condea) PEG-12 laurate Kessco ® PEG 600ML (Stepan) 15 PEG-12 oleateKessco ® PEG 600MO (Stepan) 14 PEG-12 ricinoleate (CAS #9004-97-1) >10PEG-12 stearate Mapeg ® 600 MS (PPG), Kessco ® 14 PEG 600MS (Stepan)PEG-15 stearate Nikkol TMGS-15 (Nikko), Koster K15 14 (Condea) PEG-15oleate Nikkol TMGO-15 (Nikko) 15 PEG-20 laurate Kessco ® PEG 1000 ML(Stepan) 17 PEG-20 oleate Kessco ® PEG 1000 MO (Stepan) 15 PEG-20stearate Mapeg ® 1000 MS (PPG), Kessco ® 16 PEG 1000 MS (Stepan), Myrj49 PEG-25 stearate Nikkol MYS-25 (Nikko) 15 PEG-32 laurate Kessco ® PEG1540 ML (Stepan) 16 PEG-32 oleate Kessco ® PEG 1540 MO (Stepan) 17PEG-32 stearate Kessco ® PEG 1540 MS (Stepan) 17 PEG-30 stearate Myrj51 >10 PEG-40 laurate Crodet L40 (Croda) 17.9 PEG-40 oleate Crodet O40(Croda) 17.4 PEG-40 stearate Myrj 52, Emerest ® 2715 (Henkel), >10Nikkol MYS-40 (Nikko) PEG-45 stearate Nikkol MYS-45 (Nikko) 18 PEG-50stearate Myrj 53 >10 PEG-55 stearate Nikkol MYS-55 (Nikko) 18 PEG-100oleate Crodet O-100 (Croda) 18.8 PEG-100 stearate Myrj 59, Arlacel 165(ICI) 19 PEG-200 oleate Albunol 200 MO (Taiwan Surf.) >10 PEG-400 oleateLACTOMUL (Henkel), Albunol 400 >10 MO (Taiwan Surf.) PEG-600 oleateAlbunol 600 MO (Taiwan Surf.) >10

[0035] 1.2 PEG-Fatty Acid Diesters

[0036] Polyethylene glycol fatty acid diesters are also suitable for useas surfactants in the compositions of the present invention. Among thesurfactants in Table 2, preferred hydrophilic surfactants include PEG-20dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate andPEG-32 dioleate. Representative PEG-fatty acid diesters are shown inTable 2. TABLE 2 PEG-Fatty Acid Diester Surfactants COMPOUND COMMERCIALPRODUCT (Supplier) HLB PEG-4 dilaurate Mapeg ® 200 DL (PPG), Kessco ®PEG 7 200 DL (Stepan), LIPOPEG 2-DL (Lipo Chem.) PEG-4 dioleate Mapeg ®200 DO (PPG), 6 PEG-4 distearate Kessco ® 200 DS (Stepan_(—) 5 PEG-6dilaurate Kessco ® PEG 300 DL (Stepan) 9.8 PEG-6 dioleate Kessco ® PEG300 DO (Stepan) 7.2 PEG-6 distearate Kessco ® PEG 300 DS (Stepan) 6.5PEG-8 dilaurate Mapeg ® 400 DL (PPG), Kessco ® PEG 11 400 DL (Stepan),LIPOPEG 4 DL (Lipo Chem.) PEG-8 dioleate Mapeg ® 400 DO (PPG), Kessco ®PEG 8.8 400 DO (Stepan), LIPOPEG 4 DO (Lipo Chem.) PEG-8 distearateMapeg ® 400 DS (PPG), CDS 400 (Nikkol) 11 PEG-10 dipalmitate Polyaldo2PKFG >10 PEG-12 dilaurate Kessco ® PEG 600 DL (Stepan) 11.7 PEG-12distearate Kessco ® PEG 600 DS (Stepan) 10.7 PEG-12 dioleate Mapeg ® 600DO (PPG), Kessco ® 600 10 DO(Stepan) PEG-20 dilaurate Kessco ® PEG 1000DL (Stepan) 15 PEG-20 dioleate Kessco ® PEG 1000 DO (Stepan) 13 PEG-20distearate Kessco ® PEG 1000 DS (Stepan) 12 PEG-32 dilaurate Kessco ®PEG 1540 DL (Stepan) 16 PEG-32 dioleate Kessco ® PEG 1540 DO (Stepan) 15PEG-32 distearate Kessco ® PEG 1540 DS (Stepan) 15 PEG-400 dioleateCithrol 4DO series (Croda) >10 PEG-400 distearate Cithrol 4DS series(Croda) >10

[0037] 1.3 PEG-Fatty Acid Mono- and Di-ester Mixtures

[0038] In general, mixtures of surfactants are also useful in thepresent invention, including mixtures of two or more commercialsurfactant products. Several PEG-fatty acid esters are marketedcommercially as mixtures or mono- and diesters. Representativesurfactant mixtures are shown in Table 3. TABLE 3 PEG-Fatty Acid Mono-and Diester Mixtures COMMERCIAL COMPOUND PRODUCT (Supplier) HLB PEG4-150 mono, dilaurate Kessco ® PEG 200-6000 mono, dilaurate (Stepan) PEG4-150 mono, dioleate Kessco ® PEG 200-6000 mono, dioleate (Stepan) PEG4-150 mono, distearate Kessco ® 200-6000 mono, distearate (Stepan)

[0039] 1.4 Polyethylene Glycol Glycerol Fatty Acid Esters

[0040] Suitable PEG glycerol fatty acid esters are shown in Table 4.Among the surfactants in the Table, preferred hydrophilic surfactantsare PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. TABLE 4 PEGGlycerol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLBPEG-20 glyceryl laurate Tagat ® L (Goldschmidt) 16 PEG-30 glyceryllaurate Tagat ® L2 (Goldschmidt) 16 PEG-15 glyceryl laurate Glycerox Lseries (Croda) 15 PEG-40 glyceryl laurate Glycerox L series (Croda) 15PEG-20 glyceryl stearate Capmul ® EMG (ABITEC), 13 Aldo ® MS-20 KFG(Lonza) PEG-20 glyceryl oleate Tagat ® O (Goldschmidt) >10   PEG-30glyceryl oleate Tagat ® O2 (Goldschmidt) >10  

[0041] 1.5. Alcohol-Oil Transesterification Products

[0042] A large number of surfactants of different degrees ofhydrophobicity or hydrophilicity can be prepared by reaction of alcoholsor polyalcohols with a variety of natural and/or hydrogenated oils. Mostcommonly, the oils used are castor oil or hydrogenated castor oil, or anedible vegetable oil such as corn oil, olive oil, peanut oil, palmkernel oil, apricot kernel oil, or almond oil. Preferred alcoholsinclude glycerol, propylene glycol, ethylene glycol, polyethyleneglycol, sorbitol, and pentaerythritol. Among these alcohol-oiltransesterified surfactants, preferred hydrophilic surfactants arePEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil(Cremophor RH 40), PEG-25 trioleate (TAGAT® TO), PEG-60 corn glycerides(Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel oil(Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenatedcastor oil (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labrasol),and PEG-6 caprylic/capric glycerides (Softigen 767). Preferredhydrophobic surfactants in this class include PEG-5 hydrogenated castoroil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6corn oil (Labrafil® M 2125 CS), PEG-6 almond oil (Labrafil® M 1966 CS),PEG-6 apricot kernel oil (Labrafil® M 1944 CS), PEG-6 olive oil(Labrafil® M 1980 CS), PEG-6 peanut oil (Labrafil® M 1969 CS), PEG-6hydrogenated palm kernel oil (Labrafil® M 2130 BS), PEG-6 palm kerneloil (Labrafil® M 2130 CS), PEG-6 triolein (Labrafil® M 2735 CS), PEG-8corn oil (Labrafil® WL 2609 BS), PEG-20 corn glycerides (Crovol M40),and PEG-20 almond glycerides (Crovol A40). The latter two surfactantsare reported to have HLB values of 10, which is generally considered tobe the approximate border line between hydrophilic and hydrophobicsurfactants. For purposes of the present invention, these twosurfactants are considered to be hydrophobic. Representative surfactantsof this class suitable for use in the present invention are shown inTable 5. TABLE 5 Transesterification Products of Oils and AlcoholsCOMPOUND COMMERCIAL PRODUCT (Supplier) HLB PEG-3 castor oil Nikkol CO-3(Nikko) 3 PEG-5, 9, and 16 ACCONON CA series (ABITEC) 6-7 castor oilPEG-20 castor oil Emalex C-20 (Nihon Emulsion), Nikkol 11 CO-20 TX(Nikko) PEG-23 castor oil Emulgante EL23 >10 PEG-30 castor oil EmalexC-30 (Nihon Emulsion), 11 Alkamuls ® EL 620 (Rhone-Poulenc), Incrocas 30(Croda) PEG-35 castor oil Cremophor EL and EL-P (BASF), Emulphor EL,Incrocas-35 (Croda), Emulgin RO 35 (Henkel) PEG-38 castor oil EmulganteEL 65 (Condea) PEG-40 castor oil Emalex C-40 (Nihon Emulsion), 13Alkamuls ® EL 719 (Rhone-Poulenc) PEG-50 castor oil Emalex C-50 (NihonEmulsion) 14 PEG-56 castor oil Eumulgin ® PRT 56 (Pulcra SA) >10 PEG-60castor oil Nikkol CO-60TX (Nikko) 14 PEG-100 castor oil Thomley >10PEG-200 castor oil Eumulgin ® PRT 200 (Pulcra SA) >10 PEG-5 hydrogenatedNikkol HCO-5 (Nikko) 6 castor oil PEG-7 hydrogenated Simusol ® 989(Seppic), Cremophor 6 castor oil WO7 (BASF) PEG-10 hydrogenated NikkolHCO-10 (Nikko) 6.5 castor oil PEG-20 hydrogenated Nikkol HCO-20 (Nikko)11 castor oil PEG-25 hydrogenated Simulsol ® 1292 (Seppic), Cerex ELS 11castor oil 250 (Auschem SpA) PEG-30 hydrogenated Nikkol HCO-30 (Nikko)11 castor oil PEG-40 hydrogenated Cremophor RH 40 (BASF), Croduret 13castor oil (Croda), Emulgin HRE 40 (Henkel) PEG-45 hydrogenated CerexELS 450 (Auschem Spa) 14 castor oil PEG-50 hydrogenated Emalex HC-50(Nihon Emulsion) 14 castor oil PEG-60 hydrogenated Nikkol HCO-60(Nikko); Cremophor 15 castor oil RH 60 (BASF) PEG-80 hydrogenated NikkolHCO-80 (Nikko) 15 castor oil PEG-100 hydro- Nikkol HCO-100 (Nikko) 17genated castor oil PEG-6 corn oil Labrafil ® M 2125 CS (Gattefosse) 4PEG-6 almond oil Labrafil ® M 1966 CS (Gattefosse) 4 PEG-6 apricotLabrafil ® M 1944 CS (Gattefosse) 4 kernel oil PEG-6 olive oilLabrafil ® M 1980 CS (Gattefosse) 4 PEG-6 peanut oil Labrafil ® M 1969CS (Gattefosse) 4 PEG-6 hydrogenated Labrafil ® M 2130 BS (Gattefosse) 4palm kernel oil PEG-6 palm kernel oil Labrafil ® M 2130 CS (Gattefosse)4 PEG-6 triolein Labrafil ® M 2735 CS (Gattefosse) 4 PEG-8 corn oilLabrafil ® WL 2609 BS (Gattefosse) 6-7 PEG-20 corn Crovol M40 (Croda) 10glycerides PEG-20 almond Crovol A40 (Croda) 10 glycerides PEG-25trioleate TAGAT ® TO (Goldschmidt) 11 PEG-40 palm Crovol PK-70 >10kernel oil PEG-60 corn Crovol M70(Croda) 15 glycerides PEG-60 almondCrovol A70 (Croda) 15 glycerides PEG-4 caprylic/capric Labrafac ® Hydro(Gattefosse), 4-5 triglyceride PEG-8 caprylic/capric Labrasol(Gattefosse),Labrafac CM 10 >10 glycerides (Gattefosse) PEG-6caprylic/capric SOFTIGEN ® 767 (Hüls), Glycerox 19 glycerides 767(Croda) Lauroyl macrogol-32 GELUCIRE 44/14 (Gattefosse) 14 glycerideStearoyl macrogol GELUCIRE 50/13 (Gattefosse) 13 glyceride Mono, di,tri, tetra SorbitoGlyceride (Gattefosse) <10 esters of vegetable oilsand sorbitol Pentaerythrityl Crodamol PTIS (Croda) <10 tetraisostearatePentaerythrityl Albunol DS (Taiwan Surf.) <10 distearate PentaerythritylLiponate PO-4 (Lipo Chem.) <10 tetraoleate Pentaerythrityl Liponate PS-4(Lipo Chem.) <10 tetrastearate Pentaerythrityl Liponate PE-810 (LipoChem.), <10 tetracaprylate/ Crodamol PTC (Croda) tetracapratePentaerythrityl Nikkol Pentarate 408 (Nikko) tetraoctanoate

[0043] 1.6. Polyglycerized Fatty Acids

[0044] Polyglycerol esters of fatty acids are also suitable surfactantsfor the present invention. Among the polyglyceryl fatty acid esters,preferred hydrophobic surfactants include polyglyceryl oleate (PlurolOleique), polyglyceryl-2 dioleate (Nikkol DGDO), and polyglyceryl-10trioleate. Preferred hydrophilic surfactants include polyglyceryl-10laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn1-O), and polyglyceryl-10 mono, dioleate (Caprol® PEG 860). Polyglycerylpolyricinoleates (Polymuls) are also preferred hydrophilic andhydrophobic surfactants. Examples of suitable polyglyceryl esters areshown in Table 6. TABLE 6 Polyglycerized Fatty Acids COMPOUND COMMERCIALPRODUCT (Supplier) HLB Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7 Polyglyceryl-2 NikkolDGMIS (Nikko) 5-7 isostearate Polyglyceryl-3 oleate Caprol ® 3GO(ABITEC), Drewpol 6.5 3-1-O (Stepan) Polyglyceryl-4 oleate NikkolTetraglyn 1-O (Nikko) 5-7 Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S(Nikko) 5-6 Polyglyceryl-6 oleate Drewpol 6-1-O (Stepan), Nikkol 9Hexaglyn 1-O (Nikko) Polyglyceryl-10 Nikkol Decaglyn 1-L (Nikko) 15laurate Polyglyceryl-10 oleate Nikkol Decaglyn 1-O (Nikko) 14Polyglyceryl-10 Nikkol Decaglyn 1-S (Nikko) 12 stearate Polyglyceryl-6Nikkol Hexaglyn PR-15 (Nikko) >8 ricinoleate Polyglyceryl-10 NikkolDecaglyn 1-LN (Nikko) 12 linoleate Polyglyceryl-6 Nikkol Hexaglyn 5-O(Nikko) <10 pentaoleate Polyglyceryl-3 dioleate Cremophor GO32 (BASF)<10 Polyglyceryl-3 Cremophor GS32 (BASF) <10 distearate Polyglyceryl-4Nikkol Tetraglyn 5-O (Nikko) <10 pentaoleate Polyglyceryl-6 dioleateCaprol ® 6G20 (ABITEC); Hodag 8.5 PGO-62 (Calgene), PLUROL OLEIQUE CC497 (Gattefosse) Polyglyceryl-2 dioleate Nikkol DGDO (Nikko) 7Polyglyceryl-10 Nikkol Decaglyn 3-O (Nikko) 7 trioleate Polyglyceryl-10Nikkol Decaglyn 5-O (Nikko) 3.5 pentaoleate Polyglyceryl-10 NikkolDecaglyn 7-O (Nikko) 3 septaoleate Polyglyceryl-10 Caprol ® 10G4O(ABITEC); 6.2 tetraoleate Hodag PGO-62 (CALGENE), Drewpol 10-4-O(Stepan) Polyglyceryl-10 decaisostearate Nikkol Decaglyn 10-IS (Nikko)<10 Polyglyceryl-101 Drewpol 10-10-O (Stepan), Caprol 3.5 decaoleate10G10O (ABITEC), Nikkol Decaglyn 10-O Polyglyceryl-10 mono, Caprol ® PGE860 (ABITEC) 11 dioleate Polyglyceryl Polymuls (Henkel)  3-20polyricinoleate

[0045] 1.7. Propylene Glycol Fatty Acid Esters

[0046] Esters of propylene glycol and fatty acids are suitablesurfactants for use in the present invention. In this surfactant class,preferred hydrophobic surfactants include propylene glycol monolaurate(Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propyleneglycol monooleate (Myverol P-O6), propylene glycol dicaprylate/dicaprate(Captex® 200), and propylene glycol dioctanoate (Captex® 800). Examplesof surfactants of this class are given in Table 7. TABLE 7 PropyleneGlycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLBPropylene glycol Capryol 90 (Gattefosse), Nikkol Sefsol 218 <10monocaprylate (Nikko) Propylene glycol Lauroglycol 90 (Gattefosse),Lauroglycol <10 monolaurate FCC (Gattefosse) Propylene glycol LutrolOP2000 (BASF) <10 oleate Propylene glycol Mirpyl <10 myristate Propyleneglycol ADM PGME-03 (ADM), LIPO PGMS (Lipo 3-4 monostearate Chem.),Aldo ® PGHMS (Lonza) Propylene glycol <10 hydroxy stearate Propyleneglycol PROPYMULS (Henkel) <10 ricinoleate Propylene glycol <10isostearate Propylene glycol Myverol P-O6 (Eastman) <10 monooleatePropylene glycol Captex ® 200 (ABITEC), Miglyol ® 840 >6 dicaprylate/dicaprate (Hüls), Neobee ® M-20 (Stepan) Propylene glycolCaptex ® 800 (ABITEC) >6  dioctanoate Propylene glycol LABRAFAC PG(Gattefosse) >6  caprylate/caprate Propylene glycol >6  dilauratePropylene glycol Kessco ® PGDS (Stepan) >6  distearate Propylene glycolNikkol Sefsol 228 (Nikko) >6  dicaprylate Propylene glycol Nikkol PDD(Nikko) >6  dicaprate

[0047] 1.8. Mixtures of Propylene Glycol Esters-Glycerol Esters

[0048] In general, mixtures of surfactants are also suitable for use inthe present invention. In particular, mixtures of propylene glycol fattyacid esters and glycerol fatty acid esters are suitable and arecommercially available. One preferred mixture is composed of the oleicacid esters of propylene glycol and glycerol (Arlacel 186). Examples ofthese surfactants are shown in Table 8. TABLE 8 Glycerol/PropyleneGlycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLBOleic ATMOS 300, ARLACEL 186 (ICI) 3-4 Stearic ATMOS 150 3-4

[0049] 1.9. Mono- and Diglycerides

[0050] A particularly important class of surfactants is the class ofmono- and diglycerides. These surfactants are generally hydrophobic.Preferred hydrophobic surfactants in this class of compounds includeglyceryl monooleate (Peceol), glyceryl ricinoleate, glyceryl laurate,glyceryl dilaurate (Capmul® GDL), glyceryl dioleate (Capmul® GDO),glyceryl mono/dioleate (Capmul® GMO-K), glyceryl caprylate/caprate(Capmul® MCM), caprylic acid mono/diglycerides (Imwitor® 988), and mono-and diacetylated monoglycerides (Myvacet® 9-45). Examples of thesesurfactants are given in Table 9. TABLE 9 Mono- and DiglycerideSurfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB Monopalmitolein(Larodan) <10 (C16:1) Monoelaidin (Larodan) <10 (C18:1) Monocaproin (C6)(Larodan) <10 Monocaprylin (Larodan) <10 Monocaprin (Larodan) <10Monolaurin (Larodan) <10 Glyceryl Nikkol MGM (Nikko) 3-4 monomyristate(C14) Glyceryl monooleate PECEOL (Gattefosse), Hodag GMO-D, 3-4 (C18:1)Nikkol MGO (Nikko) Glyceryl monooleate RYLO series (Danisco), DIMODAN3-4 series (Danisco), EMULDAN (Danisco), ALDO ® MO FG (Lonza), KesscoGMO (Stepan), MONOMULS ® series (Henkel), TEGIN O, DREWMULSE GMO(Stepan), Atlas G-695 (ICI), GMOrphic 80 (Eastman), ADM DMG-40, 70, and100 (ADM), Myverol (Eastman) Glycerol monooleate/ OLICINE (Gattefosse)3-4 linoleate Glycerol Maisine (Gattefosse), MYVEROL 3-4 monolinoleate18-92, Myverol 18-06 (Eastman) Glyceryl ricinoleate Softigen ® 701(Hüls), HODAG 6 GMR-D (Calgene), ALDO ® MR (Lonza) Glyceryl monolaurateALDO ® MLD (Lonza), Hodag GML 6.8 (Calgene) Glycerol Emalex GMS-P(Nihon) 4 monopalmitate Glycerol monostearate Capmul ® GMS (ABITEC),Myvaplex 5-9 (Eastman), IMWITOR ® 191 (Hüls), CUTINA GMS, Aldo ® MS(Lonza), Nikkol MGS series (Nikko) Glyceryl mono-, Capmul ® GMO-K(ABITEC) <10 dioleate Glyceiyl CUTINA MD-A, ESTAGEL-G18 <10palmitic/stearic Glyceryl acetate Lamegin ® EE (Grünau GmbH) <10Glyceryl laurate Imwitor ® 312 (Hüls), 4 Monomuls ® 90-45 (Grünau GmbH),Aldo ® MLD (Lonza) Glyceryl citrate/ Imwitor ® 375 (Hüls) <10lactate/oleate/ linoleate Glyceryl caprylate Imwitor ® 308 (Hüls),Capmul ® 5-6 MCMC8 (ABITEC) Glyceryl caprylate/ Capmul ® MCM (ABITEC)5-6 caprate Caprylic acid mono, Imwitor ® 988 (Hüls) 5-6 diglyceridesCaprylic/capric Imwitor ® 742 (Hüls) <10 glycerides Mono-anddiacetylated Myvacet ® 9-45, Myvacet ® 9-40, 3.8-4   monoglyceridesMyvacet ® 9-08 (Eastman), Lamegin ® (Grünau) Glyceryl monostearateAldo ® MS, Arlacel 129 (ICI), LIPO 4.4 GMS (Lipo Chem.), Imwitor ® 191(Hüls), Myvaplex (Eastman) Lactic acid esters of LAMEGIN GLP (Henkel)<10 mono,diglycerides Dicaproin (C6) (Larodan) <10 Dicaprin (C10)(Larodan) <10 Dioctanoin (C8) (Larodan) <10 Dimyristin (C14) (Larodan)<10 Dipalmitin (C16) (Larodan) <10 Distearin (Larodan) <10 Glyceryldilaurate Capmul ® GDL (ABITEC) 3-4 (C12) Glyceryl dioleate Capmul ® GDO(ABITEC) 3-4 Glycerol esters GELUCIRE 39/01 (Gattefosse), 1 of fattyacids GELUCIRE 43/01 (Gattefosse) GELUCIRE 37/06 (Gattefosse) 6Dipalmitolein (C16:1) (Larodan) <10 1,2 and 1,3-diolein (Larodan) <10(C18:1) Dielaidin (C18:1) (Larodan) <10 Dilinolein (C18:2) (Larodan) <10

[0051] 1.10. Sterol and Sterol Derivatives

[0052] Sterols and derivatives of sterols are suitable surfactants foruse in the present invention. These surfactants can be hydrophilic orhydrophobic. Preferred derivatives include the polyethylene glycolderivatives. A preferred hydrophobic surfactant in this class ischolesterol. A preferred hydrophilic surfactant in this class is PEG-24cholesterol ether (Solulan C-24). Examples of surfactants of this classare shown in Table 10. TABLE 10 Sterol and Sterol Derivative SurfactantsCOMPOUND COMMERCIAL PRODUCT (Supplier) HLB Cholesterol, sitosterol, <10lanosterol PEG-24 cholesterol ether Solulan C-24 (Amerchol) >10 PEG-30cholesterol Nikkol DHC (Nikko) >10 Phytosterol GENEROL series (Henkel)<10 PEG-25 phyto sterol Nikkol BPSH-25 (Nikko) >10 PEG-5 soya sterolNikkol BPS-5 (Nikko) <10 PEG-10 soya sterol Nikkol BPS-10 (Nikko) <10PEG-20 soya sterol Nikkol BPS-20 (Nikko) <10 PEG-30 soya sterol NikkolBPS-30 (Nikko) >10

[0053] 1.11. Polyethylene Glycol Sorbitan Fatty Acid Esters

[0054] A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in the present invention. In general,these surfactants are hydrophilic, although several hydrophobicsurfactants of this class can be used. Among the PEG-sorbitan fatty acidesters, preferred hydrophilic surfactants include PEG-20 sorbitanmonolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20sorbitan monostearate (Tween-60), and PEG-20 sorbitan monooleate(Tween-80). Examples of these surfactants are shown in Table 11. TABLE11 PEG-Sorbitan Fatty Acid Esters COMMERCIAL COMPOUND PRODUCT (Supplier)HLB PEG-10 sorbitan laurate Liposorb L-10 (Lipo Chem.) >10 PEG-20sorbitan monolaurate Tween-20 (Atlas/ICI), Crillet 1 17 (Croda), DACOLMLS 20 (Condea) PEG-4 sorbitan monolaurate Tween-21 (Atlas/ICI), Crillet11 13 (Croda) PEG-80 sorbitan monolaurate Hodag PSML-80 (Calgene); >10T-Maz 28 PEG-6 sorbitan monolaurate Nikkol GL-1 (Nikko) 16 PEG-20sorbitan monopalmitate Tween-40 (Atlas/ICI), Crillet 2 16 (Croda) PEG-20sorbitan monostearate Tween-60 (Atlas/ICI), Crillet 3 15 (Croda) PEG-4sorbitan monostearate Tween-61 (Atlas/ICI), Crillet 31 9.6 (Croda) PEG-8sorbitan monostearate DACOL MSS (Condea) >10 PEG-6 sorbitan monostearateNikkol TS106 (Nikko) 11 PEG-20 sorbitan tristearate Tween-65(Atlas/ICI), Crillet 35 11 (Croda) PEG-6 sorbitan tetrastearate NikkolGS-6 (Nikko) 3 PEG-60 sorbitan tetrastearate Nikkol GS-460 (Nikko) 13PEG-5 sorbitan monooleate Tween-81 (Atlas/ICI), Crillet 41 10 (Croda)PEG-6 sorbitan monooleate Nikkol TO-106 (Nikko) 10 PEG-20 sorbitanmonooleate Tween-80 (Atlas/ICI), Crillet 4 15 (Croda) PEG-40 sorbitanoleate Emalex ET 8040 18 (Nihon Emulsion) PEG-20 sorbitan trioleateTween-85 (Atlas/ICI), Crillet 45 11 (Croda) PEG-6 sorbitan tetraoleateNikkol GO-4 (Nikko) 8.5 PEG-30 sorbitan tetraoleate Nikkol GO-430(Nikko) 12 PEG-40 sorbitan tetraoleate Nikkol GO-440 (Nikko) 13 PEG-20sorbitan Tween-120 (Atlas/ICI), Crillet 6 >10 monoisostearate (Croda)PEG sorbitol hexaoleate Atlas G-1086 (ICI) 10 PEG-6 sorbitolhexastearate Nikkol GS-6 (Nikko) 3

[0055] 1.12. Polyethylene Glycol Alkyl Ethers

[0056] Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in the present invention. Preferred hydrophobicethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij30). Examples of these surfactants are shown in Table 12. TABLE 12Polyethylene Glycol Alkyl Ethers COMMERCIAL COMPOUND PRODUCT (Supplier)HLB PEG-2 oleyl ether,oleth-2 Brij 92/93 (Atlas/ICI) 4.9 PEG-3 oleylether,oleth-3 Volpo 3 (Croda) <10 PEG-5 oleyl ether,oleth-5 Volpo 5(Croda) <10 PEG-10 oleyl ether,oleth-10 Volpo 10 (Croda), Brij 96/97 12(Atlas/ICI) PEG-20 oleyl ether,oleth-20 Volpo 20 (Croda), Brij 98/99 15(Atlas/ICI) PEG-4 lauryl ether, laureth-4 Brij 30 (Atlas/ICI) 9.7 PEG-9lauryl ether >10 PEG-23 lauryl ether, laureth-23 Brij 35 (Atlas/ICI) 17PEG-2 cetyl ether Brij 52 (ICI) 5.3 PEG-10 cetyl ether Brij 56 (ICI) 13PEG-20 cetyl ether Brij 58 (ICI) 16 PEG-2 stearyl ether Brij 72 (ICI)4.9 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-20 stearyl ether Brij 78(ICI) 15 PEG-100 stearyl ether Brij 700 (ICI) >10

[0057] 1.13. Sugar Esters

[0058] Esters of sugars are suitable surfactants for use in the presentinvention. Preferred hydrophilic surfactants in this class includesucrose monopalmitate and sucrose monolaurate. Examples of suchsurfactants are shown in Table 13. TABLE 13 Sugar Ester SurfactantsCOMPOUND COMMERCIAL PRODUCT (Supplier) HLB Sucrose distearate SUCROESTER 7 (Gattefosse), 3 Crodesta F-10 (Croda) Sucrose distearate/ SUCROESTER 11 (Gattefosse), 12 monostearate Crodesta F-110 (Croda) Sucrosedipalmitate 7.4 Sucrose monostearate Crodesta F-160 (Croda) 15 Sucrosemonopalmitate SUCRO ESTER 15 (Gattefosse) >10 Sucrose monolaurateSaccharose monolaurate 15 1695 (Mitsubishi-Kasei)

[0059] 1.14. Polyethylene Glycol Alkyl Phenols

[0060] Several hydrophilic PEG-alkyl phenol surfactants are available,and are suitable for use in the present invention. Examples of thesesurfactants are shown in Table 14. TABLE 14 Polyethylene Glycol AlkylPhenol Surfactants COMMERCIAL COMPOUND PRODUCT (Supplier) HLB PEG-10-100nonyl phenol Triton X series (Rohm & Haas), >10 Igepal CA series (GAF,USA), Antarox CA series (GAF, UK) PEG-15-100 octyl phenol ether TritonN-series (Rohm & Haas), >10 Igepal CO series (GAF, USA), Antarox COseries (GAF, UK)

[0061] 1.15. Polyoxyethylene-Polyoxypropylene Block Copolymers

[0062] The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and hydrophobic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in the presentinvention. These surfactants are available under various trade names,including Synperonic PE series (ICI); Pluronic® series (BASF), Emkalyx,Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The genericterm for these polymers is “poloxamer” (CAS 9003-11-6). These polymershave the formula:

HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(n)H

[0063] where “a” and “b” denote the number of polyoxyethylene andpolyoxypropylene units, respectively.

[0064] Preferred hydrophilic surfactants of this class includePoloxamers 108, 188, 217, 238, 288, 338, and 407. Preferred hydrophobicsurfactants in this class include Poloxamers 124, 182, 183, 212, 331,and 335.

[0065] Examples of suitable surfactants of this class are shown in Table15. Since the compounds are widely available, commercial sources are notlisted in the Table. The compounds are listed by generic name, with thecorresponding “a” and “b” values. TABLE 15 POE-POP Block Copolymers a, bvalues in COMPOUND HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H HLB Poloxamer105 a = 11 b = 16 8 Poloxamer 108 a = 46 b = 16 >10 Poloxamer 122 a = 5b = 21 3 Poloxamer 123 a = 7 b = 21 7 Poloxamer 124 a = 11 b = 21 >7Poloxamer 181 a = 3 b = 30 Poloxamer 182 a = 8 b = 30 2 Poloxamer 183 a= 10 b = 30 Poloxamer 184 a = 13 b = 30 Poloxamer 185 a = 19 b = 30Poloxamer 188 a = 75 b = 30 29 Poloxamer 212 a = 8 b = 35 Poloxamer 215a = 24 b = 35 Poloxamer 217 a = 52 b = 35 Poloxamer 231 a = 16 b = 39Poloxamer 234 a = 22 b = 39 Poloxamer 235 a = 27 b = 39 Poloxamer 237 a= 62 b = 39 24 Poloxamer 238 a = 97 b = 39 Poloxamer 282 a = 10 b = 47Poloxamer 284 a = 21 b = 47 Poloxamer 288 a = 122 b = 47 >10 Poloxamer331 a = 7 b = 54 0.5 Poloxamer 333 a = 20 b = 54 Poloxamer 334 a = 31 b= 54 Poloxamer 335 a = 38 b = 54 Poloxamer 338 a = 128 b = 54 Poloxamer401 a = 6 b = 67 Poloxamer 402 a = 13 b = 67 Poloxamer 403 a = 21 b = 67Poloxamer 407 a = 98 b = 67

[0066] 1.16. Sorbitan Fatty Acid Esters

[0067] Sorbitan esters of fatty acids are suitable surfactants for usein the present invention. Among these esters, preferred hydrophobicsurfactants include sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitanmonostearate, and sorbitan tristearate. Examples of these surfactantsare shown in Table 16. TABLE 16 Sorbitan Fatty Acid Ester SurfactantsCOMPOUND COMMERCIAL PRODUCT (Supplier) HLB Sorbitan monolaurate Span-20(Atlas/ICI), Crill 1 (Croda), 8.6 Arlacel 20 (ICI) Sorbitanmonopalmitate Span-40 (Atlas/ICI), Crill 2 (Croda), 6.7 Nikkol SP-10(Nikko) Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 (Croda), 4.3Crill 50 (Croda) Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3(Croda), 4.7 Nikkol SS-10 (Nikko) Sorbitan trioleate Span-85(Atlas/ICI), Crill 45 (Croda), 4.3 Nikkol SO-30 (Nikko) Sorbitansesquioleate Arlacel-C (ICI), Crill 43 (Croda), 3.7 Nikkol SO-15 (Nikko)Sorbitan tristearate Span-65 (Atlas/ICI) Crill 35 (Croda), 2.1 NikkolSS-30 (Nikko) Sorbitan monoisostearate Crill 6 (Croda), Nikkol SI-10(Nikko) 4.7 Sorbitan sesquistearate Nikkol SS-15 (Nikko) 4.2

[0068] 1.17. Lower Alcohol Fatty Acid Esters

[0069] Esters of lower alcohols (C₂ to C₄) and fatty acids (C₈ to C₁₈)are suitable surfactants for use in the present invention. Among theseesters, preferred hydrophobic surfactants include ethyl oleate (CrodamolEO), isopropyl myristate (Crodamol IPM), and isopropyl palmitate(Crodamol IPP). Examples of these surfactants are shown in Table 17.TABLE 17 Lower Alcohol Fatty Acid Ester Surfactants COMPOUND COMMERCIALPRODUCT (Supplier) HLB Ethyl oleate Crodamol EO (Croda), Nikkol EOO(Nikko) <10 Isopropyl myristate Crodamol IPM (Croda) <10 Isopropylpalmitate Crodamol IPP (Croda) <10 Ethyl linoleate Nikkol VF-E (Nikko)<10 Isopropyl linoleate Nikkol VF-IP (Nikko) <10

[0070] 1.18. Ionic Surfactants

[0071] Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in the presentinvention. Preferred anionic surfactants include fatty acid salts andbile salts. Specifically, preferred ionic surfactants include sodiumoleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, sodium cholate, and sodium taurocholate. Examples ofsuch surfactants are shown in Table 18 below. For simplicity, typicalcounterions are shown in the entries in the Table. It will beappreciated by one skilled in the art, however, that any bioacceptablecounterion may be used. For example, although the fatty acids are shownas sodium salts, other cation counterions can also be used, such asalkali metal cations or ammonium. Unlike typical non-ionic surfactants,these ionic surfactants are generally available as pure compounds,rather than commercial (proprietary) mixtures. Because these compoundsare readily available from a variety of commercial suppliers, such asAldrich, Sigma, and the like, commercial sources are not generallylisted in the Table. TABLE 18 Ionic Surfactants COMPOUND HLB FATTY ACIDSALTS >10 Sodium caproate Sodium caprylate Sodium caprate Sodium laurateSodium myristate Sodium myristolate Sodium palmitate Sodium palmitoleateSodium oleate 18 Sodium ricinoleate Sodium linoleate Sodium linolenateSodium stearate Sodium lauryl sulfate (dodecyl) 40 Sodium tetradecylsulfate Sodium lauryl sarcosinate Sodium dioctyl sulfosuccinate [sodiumdocusate (Cytec)] BILE SALTS >10 Sodium cholate Sodium taurocholateSodium glycocholate Sodium deoxycholate Sodium taurodeoxycholate Sodiumglycodeoxycholate Sodium ursodeoxycholate Sodium chenodeoxycholateSodium taurochenodeoxycholate Sodium glyco cheno deoxycholate Sodiumcholylsarcosinate Sodium N-methyl taurocholate PHOSPHOLIPIDS Egg/Soylecithin [Epikuron ™ (Lucas Meyer), Ovothin ™ (Lucas Meyer)] Lysoegg/soy lecithin Hydroxylated lecithin LysophosphatidylcholineCardiolipin Sphingomyelin Phosphatidylcholine Phosphatidyl ethanolaminePhosphatidic acid Phosphatidyl glycerol Phosphatidyl serine PHOSPHORICACID ESTERS Diethanolammonium polyoxyethylene-10 oleyl ether phosphateEsterification products of fatty alcohols or fatty alcohol ethoxylateswith phosphoric acid or anhydride CARBOXYLATES Ether carboxylates (byoxidation of terminal OH group of fatty alcohol ethoxylates)Succinylated monoglycerides [LAMEGIN ZE (Henkel)] Sodium stearylfumarate Stearoyl propylene glycol hydrogen succinate Mono/diacetylatedtartaric acid esters of mono- and diglycerides Citric acid esters ofmono-, diglycerides Glyceryl-lacto esters of fatty acids (CFR ref.172.852) Acyl lactylates: lactylic esters of fatty acids calcium/sodiumstearoyl-2-lactylate calcium/sodium stearoyl lactylate Alginate saltsPropylene glycol alginate SULFATES AND SULFONATES Ethoxylated alkylsulfates Alkyl benzene sulfones α-olefin sulfonates Acyl isethionatesAcyl taurates Alkyl glyceryl ether sulfonates Octyl sulfosuccinatedisodium Disodium undecylenamideo-MEA-sulfosuccinate CATIONICSurfactants >10 Hexadecyl triammonium bromide Decyl trimethyl ammoniumbromide Cetyl trimethyl ammonium bromide Dodecyl ammonium chloride Alkylbenzyldimethylammonium salts Diisobutyl phenoxyethoxydimethylbenzylammonium salts Alkylpyridinium salts Betaines (trialkylglycine):Lauryl betaine (N-lauryl,N,N-dimethylglycine) Ethoxylated amines:Polyoxyethylene-15 coconut amine

[0072] 1.19 Surfactant Concentrations

[0073] The hydrophilic and hydrophobic surfactants are present in thepharmaceutical compositions of the present invention in amounts suchthat upon dilution with an aqueous solution, the carrier forms a clear,aqueous dispersion of the hydrophilic and hydrophobic surfactants,containing the hydrophobic therapeutic agent. The relative amounts ofhydrophilic and hydrophobic surfactants are readily determined byobserving the properties of the resultant dispersion; i.e., when therelative amounts of the hydrophobic and hydrophilic surfactants arewithin a suitable range, the resultant aqueous dispersion is opticallyclear. When the relative amount of hydrophobic surfactant is too great,the resulting dispersion is visibly “cloudy”, resembling a conventionalemulsion or multiple phase system. Although a visibly cloudy solutionmay be potentially useful for some applications, such a system wouldsuffer from many of the same disadvantages as conventional prior artformulations, as described above.

[0074] A convenient method of determining the appropriate relativeconcentrations for any hydrophilic surfactant-hydrophobic surfactantpair is as follows. A convenient working amount of a hydrophilicsurfactant is provided, and a known amount of a hydrophobic surfactantis added. The surfactants are stirred to form a homogeneous mixture,with the aid of gentle heating if desired. The resulting mixture isdiluted with purified water to prepare an aqueous dispersion. Anydilution amount can be chosen, but convenient dilutions are those withinthe range expected in vivo, about a 10 to 250-fold dilution. The aqueousdispersion is then assessed qualitatively for optical clarity. Theprocedure can be repeated with incremental variations in the relativeamount of hydrophobic surfactant added, to determine the maximumrelative amount of hydrophobic surfactant that can be present for agiven surfactant pair.

[0075] Alternatively, the optical clarity of the aqueous dispersion canbe measured using standard quantitative techniques for turbidityassessment. One convenient procedure to measure turbidity is to measurethe amount of light of a given wavelength transmitted by the solution,using, for example, a UV-visible spectrophotometer. Using this measure,optical clarity corresponds to high transmittance, since cloudiersolutions will scatter more of the incident radiation, resulting inlower transmittance measurements. If this procedure is used, care shouldbe taken to insure that the surfactant mixture does not itself absorblight of the chosen wavelength, as any true absorbance necessarilyreduces the amount of transmitted light and falsely increases thequantitative turbidity value. In the absence of chromophores at thechosen wavelength, suitable dispersions at a dilution of 10× should havean apparent absorbance of less than about 0.3, preferably less thanabout 0.2, and more preferably less than about 0.1. At a dilution of100×, suitable dispersions should have an apparent absorbance of lessthan about 0.1, preferably less than about 0.05, and more preferablyless than about 0.01.

[0076] A third method of determining optical clarity and carrierdiffusivity through the aqueous boundary layer is to quantitativelymeasure the size of the particles of which the dispersion is composed.These measurements can be performed on commercially available particlesize analyzers, such as, for example, a Nicomp particle size analyzeravailable from Particle Size Systems, Inc., of Santa Barbara, Calif.Using this measure, clear aqueous dispersions according to the presentinvention have average particle sizes much smaller than the wavelengthof visible light, whereas dispersions containing excessive relativeamounts of the hydrophobic surfactant have more complex particle sizedistributions, with much greater average particle sizes. It is desirablethat the average particle size be less than about 100 nm, preferablyless than about 50 nm, more preferably less than about 30 nm, and stillmore preferably less than about 20 nm. It is also preferred that theparticle size distribution be mono-modal. As is shown in more detail inthe Examples herein, dispersions having an undesirably large relativeamount of hydrophobic surfactant typically display bimodal particle sizedistributions, such distributions having a small particle sizecomponent, typically less than about 30 nm, and a large particle sizecomponent, typically on the order of 100 nm or more. It should beemphasized that these particle sizes are appropriate for the carrierparticles in aqueous solution, in the absence of a hydrophobictherapeutic agent. It is expected that the presence of the hydrophobictherapeutic agent may result in an increase in the average particlesize.

[0077] Other methods of determining optical clarity or particle size canbe used as desired. Such methods are well know to those skilled in theart.

[0078] It should be emphasized that any or all of the available methodsmay be used to ensure that the resulting aqueous dispersions possess therequisite optical clarity. For convenience, however, the presentinventors prefer to use the simple qualitative procedure; i.e., simplevisible observation. However, in order to more fully illustrate thepractice of the present invention, all three of the above measures areused to assess the dispersion clarity in the Examples herein.

[0079] Although it should be understood that any aqueous dispersionhaving the properties described above is within the scope of the presentinvention regardless of the specific relative amounts of hydrophobic andhydrophilic surfactants, it is expected that the amount of hydrophobicsurfactant will generally be less than about 200% by weight, based onthe amount of hydrophilic surfactant, and more specifically, in therange of about 1% to 200%. Further, based on observations reported inthe Examples herein, it is expected that the amount of hydrophobicsurfactant will generally be less than about 100%, and more specificallyin the range of about 5% to about 100% by weight, or about 10% to about100% by weight, based on the amount of hydrophilic surfactant. For someparticular surfactant combinations, cloudy solutions result when theamount of hydrophobic surfactant is greater than about 60% by weight,based on the amount of hydrophilic surfactant. A preferred range forthese surfactants is about 1% to about 60%, preferably about 5% to about60%, and more preferably about 10% to about 60%. Addition of optionalexcipients as described below can further increase the maximum relativeamount of hydrophobic surfactant that can be used.

[0080] Other considerations well known to those skilled in the art willfurther inform the choice of specific proportions of hydrophobic andhydrophilic surfactants. These considerations include the degree ofbioacceptability of the surfactants, and the desired dosage ofhydrophobic therapeutic agent to be provided. In some cases, the amountof hydrophobic surfactant actually used in a pharmaceutical compositionaccording to the present invention will be less than the maximum thatcan be used, and it should be apparent that such compositions are alsowithin the scope of the present invention.

[0081] 2. Hydrophobic Therapeutic Agents

[0082] Hydrophobic therapeutic agents suitable for use in thepharmaceutical compositions of the present invention are notparticularly limited, as the carrier is surprisingly capable ofsolubilizing and delivering a wide variety of hydrophobic therapeuticagents. Hydrophobic therapeutic agents are compounds with little or nowater solubility. Intrinsic water solubilities (i.e., water solubilityof the unionized form) for hydrophobic therapeutic agents usable in thepresent invention are less than about 1% by weight, and typically lessthan about 0.1% or 0.01% by weight. Such therapeutic agents can be anyagents having therapeutic or other value when administered to an animal,particularly to a mammal, such as drugs, nutrients, and cosmetics(cosmeceuticals). It should be understood that while the invention isdescribed with particular reference to its value in the form of aqueousdispersions, the invention is not so limited. Thus, hydrophobic drugs,nutrients or cosmetics which derive their therapeutic or other valuefrom, for example, topical or transdermal administration, are stillconsidered to be suitable for use in the present invention.

[0083] Specific non-limiting examples of hydrophobic therapeutic agentsthat can be used in the pharmaceutical compositions of the presentinvention include the following representative compounds, as well astheir pharmaceutically acceptable salts, isomers, esters, ethers andother derivatives:

[0084] analgesics and anti-inflammatory agents, such as aloxiprin,auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac,diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen,ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide,meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin,oxyphenbutazone, phenylbutazone, piroxicam, refocoxib, sulindac,tetrahydrocannabinol, tramadol and tromethamine;

[0085] anthelmintics, such as albendazole, bephenium hydroxynaphthoate,cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine,oxfendazole, oxantel embonate, praziquantel, pyrantel embonate andthiabendazole;

[0086] anti-arrhythmic agents, such as amiodarone HCl, disopyramide,flecainide acetate and quinidine sulfate;

[0087] anti-asthma agents, such as zileuton, zafirlukast, terbutalinesulfate, montelukast, and albuterol;

[0088] anti-bacterial agents, such as alatrofloxacin, azithromycin,baclofen, benethamine penicillin, cinoxacin, ciprofloxacin HCl,clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin,doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin,imipenem, levofloxacin, lorefloxacin, moxifloxacin HCl, nalidixic acid,nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutine,rifapentine, sparfloxacin, spiramycin, sulphabenzamide, sulphadoxine,sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole,sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim,trovafloxacin, and vancomycin;

[0089] anti-viral agents, such as abacavir, amprenavir, delavirdine,efavirenz, indivir, lamivudine, nelfinavir, nevirapine, ritonavir,saquinavir, and stavueline;

[0090] anti-coagulants, such as cilostazol, clopidrogel, dicoumarol,dipyridamole, nicoumalone, oprelvekin, phenindione, ticlidopine, andtirofibran;

[0091] anti-depressants, such as amoxapine, bupropion, citalopram,clomipramine, fluexetine HCl, maprotiline HCl, mianserin HCl,nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl,trimipramine maleate, and venlafaxine HCl;

[0092] anti-diabetics, such as acetohexamide, chlorpropamide,glibenclamide, gliclazide, glipizide, glymepride, miglitol,pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide andtroglitazone;

[0093] anti-epileptics, such as beclamide, carbamazepine, clonazepam,ethotoin, felbamate, fosphenytoin sodium, lamotrigine, methoin,methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione,phenacemide, phenobarbitone, phenytoin, phensuximide, primidone,sulthiame, tiagabine HCl, topiramate, valproic acid, and vigabatrin;

[0094] anti-fungal agents, such as amphotericin, butenafine HCl,butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole,flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole,natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine HCl,terconazole, tioconazole and undecenoic acid;

[0095] anti-gout agents, such as allopurinol, probenecid andsulphin-pyrazone;

[0096] anti-hypertensive agents, such as amlodipine, benidipine,benezepril, candesartan, captopril, darodipine, dilitazem HCl,diazoxide, doxazosin HCl, elanapril, eposartan losartan, mesylate,felodipine, fenolclopam, fosinopril, guanabenz acetate, irbesartan,isradipine, lisinopril, minoxidil, nicardipine HCl, nifedipine,nimodipine, nisolidipine, phenoxybenzamine HCl, prazosin HCl, quinapril,reserpine, terazosin HCl, telmisartan, and valsartan;

[0097] anti-malarials, such as amodiaquine, chloroquine, chlorproguanilHCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine andquinine sulfate;

[0098] anti-migraine agents, such as dihydroergotamine mesylate,ergotamine tartrate, frovatriptan, methysergide maleate, naratriptanHCl, pizotifen maleate, rizatriptan benzoate, sumatriptan succinate, andzolmitriptan;

[0099] anti-muscarinic agents, such as atropine, benzhexol HCl,biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide,oxyphencylcimine HCl and tropicamide;

[0100] anti-neoplastic agents and immunosuppressants, such asaminoglutethimide, amsacrine, azathioprine, bicalutamide, bisanthrene,busulphan, camptothecan, capecitabine, chlorambucil, cyclosporin,dacarbazine, ellipticine, estramustine, etoposide, irinotecan,lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,mitoxantrone, mofetil, mycophenolate, nilutamide, paclitaxel,procarbazine HCl, sirolimus, tacrolimus, tamoxifen citrate, teniposide,testolactone, topotecan HCl, and toremifene citrate;

[0101] anti-protozoal agents, such as atovaquone, benznidazole,clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate,dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone,omidazole and tinidazole;

[0102] anti-thyroid agents, such as carbimazole, paricalcitol, andpropylthiouracil;

[0103] anti-tussives, such as benzonatate;

[0104] anxiolytic, sedatives, hypnotics and neuroleptics, such asalprazolam, amylobarbitone, barbitone, bentazepam, bromazepam,bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide,chlormethiazole, chlorpromazine, chlorprothiocene, clonazepam, clobazam,clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone,flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazinedecanoate, flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam,medazepam, meprobamate, mesoridiazine, methaqualone, methyl phenidate,midazolam, molindone, nitrazepam, olanzapine, oxazepam, pentobarbitone,perphenazine pimozide, prochlorperazine, pseudo-ephedrine, quetiapine,risperodone, sertindole, sulpiride, temazepam, thioridazine, triazolam,zolpidem, and zopiclone;

[0105] β-Blockers, such as acebutolol, alprenolol, atenolol, labetalol,metoprolol, nadolol, oxprenolol, pindolol and propranolol;

[0106] cardiac inotropic agents, such as amrinone, digitoxin, digoxin,enoximone, lanatoside C and medigoxin;

[0107] corticosteroids, such as beclomethasone, betamethasone,budesonide, cortisone acetate, desoxymethasone, dexamethasone,fludrocortisone acetate, flunisolide, flucortolone, fluticasonepropionate, hydrocortisone, methylprednisolone, prednisolone, prednisoneand triamcinolone;

[0108] diuretics, such as acetazolamide, amiloride, bendrofluazide,bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide,metolazone, spironolactone and triamterene.

[0109] anti-parkinsonian agents, such as bromocriptine mesylate,lysuride maleate, pramipexole, robinirole HCl, and tolcapone;

[0110] gastro-intestinal agents, such as bisacodyl, cimetidine,cisapride, diphenoxylate HCl, domperidone, famotidine, lanosprazole,loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCL,rabeprazole sodium, ranitidine HCl and sulphasalazine;

[0111] histamine H,-receptor antagonists, such as acrivastine,astemizole, chlophenisamine, cinnarizine, citrizine, clemastinefumarate, cyclizine, cyproheptadine HCl, dexchlopheniramine,dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclozineHCl, oxatomide, and terenadine;

[0112] keratolytics, such as acutretin, calciprotiene, calcifediol,calcitriol, cholecalciferol, ergocalciferol, etretinate, retinoids,targretin, and tazarotene;

[0113] lipid regulating agents, such as atorvastatin, bezafibrate,cerivistatin, clinofibrate, clofibrate, fenofibrate, fluvastatin,gemfibrozil, pravastatin, probucol, and simvastatin;

[0114] muscle relaxants, such as dantrolene sodium and tizanidine HCl;

[0115] nitrates and other anti-anginal agents, such as amyl nitrate,glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate andpentaerythritol tetranitrate;

[0116] nutritional agents, such as calcitriol, carotenes,dihydrotachysterol, essential fatty acids, non-essential fatty acids,phytonodione, vitamin A, vitamin B₂, vitamin D, vitamin E and vitamin K.

[0117] opioid analgesics, such as codeine, dextropropyoxyphene,diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone, morphine,nalbuphine and pentazocine;

[0118] sex hormones, such as clomiphene citrate, cortisone acetate,danazol, dihydro epiandrosterone, ethinyloestradiol, finasteride,fludrocortisone, fluoxymisterone, medroxyprogesterone acetate,megesterol acetate, mestranol, methyltestosterone, norethisterone,norgestrel, oestradiol, conjugated estrogens, progesterone, rimexolone,stanozolol, stiboestrol, testosterone and tibolone;

[0119] stimulants, such as amphetamine, dexamphetamine, dexfenfluramine,fenfluramine and mazindol;

[0120] and others, such as becaplermin, donepezil HCl, L-thryroxine,methoxsalen, nerteporfin, physostigmine, pyridostigmine, raloxifene HCl,sibutramine HCl, sildenafil citrate, tacrine, tamsulosin HCl, andtolterodine.

[0121] Preferred hydrophobic therapeutic agents include sildenafilcitrate, amlodipine, tramadol, celecoxib, refocoxib, oxaprozin,nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast,cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine,loratadine, famotidine, paricalcitol, atovaquone, nabumetone,tetrahydrocannabinol, megesterol acetate, repaglinide, progesterone,rimexolone, cyclosporine, tacrolimus, sirolimus, teniposide, paclitaxel,pseudo-ephedrine, troglitazone, rosiglitazone, finasteride, vitamin A,vitamin D, vitamin E, and pharmaceutically acceptable salts, isomers andderivatives thereof. Particularly preferred hydrophobic therapeuticagents are progesterone and cyclosporin.

[0122] It should be appreciated that this listing of hydrophobictherapeutic agents and their therapeutic classes is merely illustrative.Indeed, a particular feature, and surprising advantage, of thecompositions of the present invention is the ability of the presentcompositions to solubilize and deliver a broad range of hydrophobictherapeutic agents, regardless of functional class. Of course, mixturesof hydrophobic therapeutic agents may also be used where desired.

[0123] 3. Solubilizers

[0124] If desired, the pharmaceutical compositions of the presentinvention can optionally include additional compounds to enhance thesolubility of the hydrophobic therapeutic agent in the carrier system.Examples of such compounds, referred to as “solubilizers”, include:

[0125] alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;

[0126] ethers of polyethylene glycols having an average molecular weightof about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol, available commercially from BASF under the trade nameTetraglycol) or methoxy PEG (Union Carbide);

[0127] amides, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone;

[0128] esters, such as ethyl propionate, tributylcitrate, acetyltriethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate,ethyl caprylate, ethyl butyrate, triacetin, propylene glycolmonoacetate, propylene glycol diacetate, ε-caprolactone and isomersthereof, δ-valerolactone and isomers thereof, β-butyrolactone andisomers thereof;

[0129] and other solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methylpyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycolmonoethyl ether (available from Gattefosse under the trade nameTranscutol), and water.

[0130] Mixtures of solubilizers are also within the scope of theinvention. Except as indicated, these compounds are readily availablefrom standard commercial sources.

[0131] Preferred solubilizers include triacetin, triethylcitrate, ethyloleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethyleneglycol 200-600, glycofurol, transcutol, propylene glycol, and dimethylisosorbide. Particularly preferred solubilizers include sorbitol,glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propyleneglycol.

[0132] The amount of solubilizer that can be included in compositions ofthe present invention is not particularly limited. Of course, when suchcompositions are ultimately administered to a patient, the amount of agiven solubilizer is limited to a bioacceptable amount, which is readilydetermined by one of skill in the art. In some circumstances, it may beadvantageous to include amounts of solubilizers far in access ofbioacceptable amounts in order to maximize the concentration ofhydrophobic therapeutic agent, with excess solubilizer removed prior toproviding the composition to a patient using conventional techniques,such as distillation or evaporation. Thus, if present, the solubilizercan be in a concentration of 50%, 100%, 200%, or up to about 400% byweight, based on the amount of surfactant. If desired, very smallamounts of solubilizers may also be used, such as 25%, 10%, 5%, 1% oreven less. Typically, the solubilizer will be present in an amount ofabout 1% to about 100%, more typically about 5% to about 25% by weight.

[0133] 4. Other Additives

[0134] Other additives conventionally used in pharmaceuticalcompositions can be included, and these additives are well known in theart. Such additives include antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants odorants,opacifiers, suspending agents, binders, and mixtures thereof. Theamounts of such additives can be readily determined by one skilled inthe art, according to the particular properties desired.

[0135] 5. Dosage Forms

[0136] The pharmaceutical compositions of the present invention can beprovided in the form of a solution preconcentrate; i.e., a compositionas described above, and intended to be dispersed with water, eitherprior to administration, in the form of a drink, or dispersed in vivo.Alternatively, the compositions can be provided in the form of a dilutedpreconcentrate (i.e., an aqueous dispersion), a semi-solid dispersion ora solid dispersion. If desired, the compositions may be encapsulated ina hard or soft gelatin capsule, a starch capsule or an enteric coatedcapsule. The term “enteric coated capsule” as used herein means acapsule coated with a coating resistant to acid; i.e., an acid resistantenteric coating. Although solubilizers are typically used to enhance thesolubility of a hydrophobic therapeutic agent, they may also render thecompositions more suitable for encapsulation in hard or soft gelatincapsules. Thus, the use of a solubilizer such as those described aboveis particularly preferred in capsule dosage forms of the pharmaceuticalcompositions. If present, these solubilizers should be added in amountssufficient to impart to the compositions the desired solubilityenhancement or encapsulation properties.

[0137] Although formulations specifically suited to oral administrationare presently preferred, the compositions of the present invention canalso be formulated for topical, transdermal, ocular, pulmonary, vaginal,rectal, transmucosal or parenteral administration, in the form of atriglyceride-free cream, lotion, ointment, suppository, gel or the like.If such a formulation is desired, other additives may be included, suchas are well-known in the art, to impart the desired consistency andother properties to the formulation. The compositions of the presentinvention can also be formulated as a spray or an aerosol. Inparticular, the compositions may be formulated as a sprayable solution,and such formulation is particularly useful for spraying to coat amultiparticulate carrier, such as a bead. Such multiparticulate carriersare well known in the art.

[0138] 6. Preparation of Pharmaceutical Compositions

[0139] The pharmaceutical compositions of the present invention can beprepared by conventional methods well known to those skilled in the art.Of course, the specific method of preparation will depend upon theultimate dosage form. For dosage forms substantially free of water,i.e., when the composition is provided in a pre-concentrated form forlater dispersion in an aqueous system, the composition is prepared bysimple mixing of the components to form a pre-concentrate. The mixingprocess can be aided by gentle heating, if desired. For compositions inthe form of an aqueous dispersion, the pre-concentrate form is prepared,then the appropriate amount of purified water is added. Upon gentlemixing, a clear aqueous dispersion is formed. If any water-solubleadditives are included, these may be added first as part of thepre-concentrate, or added later to the clear aqueous dispersion, asdesired.

[0140] In another embodiment, the present invention includes amulti-phase dispersion. In this embodiment, a pharmaceutical compositionincludes a carrier which forms a clear aqueous dispersion upon mixingwith an aqueous solution, and an additional amount of non-solubilizedhydrophobic therapeutic agent. Thus, the term “multi-phase” as usedherein to describe these compositions of the present invention means acomposition which when mixed with an aqueous solution forms a clearaqueous phase and a particulate dispersion phase. The carrier is asdescribed above, and can include any of the surfactants, hydrophobictherapeutic agents, solubilizers and additives previously described. Anadditional amount of hydrophobic therapeutic agent is included in thecomposition. This additional amount is not solubilized by the carrier,and upon mixing with an aqueous system is present as a separatedispersion phase. The additional amount is optionally a milled,micronized, or precipitated form. Thus, upon dilution, the compositioncontains two phases: a clear aqueous dispersion of the hydrophilic andhydrophobic surfactants containing a first, solubilized amount of thehydrophobic therapeutic agent, and a second, non-solubilized amount ofthe hydrophobic therapeutic agent dispersed therein. It should beemphasized that the resultant multi-phase dispersion will not have theoptical clarity of a dispersion in which the hydrophobic therapeuticagent is fully solubilized, but will appear to be cloudy, due to thepresence of the non-solubilized phase. Such a formulation may be useful,for example, when the desired dosage of a hydrophobic therapeutic agentexceeds that which can be solubilized in the carrier of the presentinvention. The formulation may also contain additives, as describedabove.

[0141] One skilled in the art will appreciate that a hydrophobictherapeutic agent may have a greater solubility in the pre-concentratecarrier than in the aqueous dispersion, so that meta-stable,supersaturated solutions having apparent optical clarity but containinga hydrophobic therapeutic agent in an amount in excess of its solubilityin the aqueous dispersion can be formed. Such super-saturated solutions,whether characterized as clear aqueous dispersions (as initially formed)or as multi-phase solutions (as would be expected if the meta-stablestate breaks down), are also within the scope of the present invention.

[0142] The multi-phase formulation can be prepared by the methodsdescribed above. A pre-concentrate is prepared by simple mixing of thecomponents, with the aid of gentle heating, if desired. It is convenientto consider the hydrophobic therapeutic agent as divided into twoportions, a first solubilizable portion which will be solubilized by thecarrier and contained within the clear aqueous dispersion upon dilution,and a second non-solubilizable portion which will remainnon-solubilized. When the ultimate dosage form is non-aqueous, the firstand second portions of the hydrophobic therapeutic agent are bothincluded in the pre-concentrate mixture. When the ultimate dosage formis aqueous, the composition can be prepared in the same manner, and upondilution in an aqueous system, the composition will form the two phasesas described above, with the second non-solubilizable portion of thehydrophobic therapeutic agent dispersed or suspended in the aqueoussystem, and the first solubilizable portion of the hydrophobictherapeutic agent solubilized in the mixed surfactant carrier.Alternatively, when the ultimate dosage form is aqueous, thepre-concentrate can be prepared including only the first, solubilizableportion of the hydrophobic therapeutic agent. This pre-concentrate canthen be diluted in an aqueous system to form a clear aqueous dispersion,to which is then added the second, non-solubilizable portion of thehydrophobic therapeutic agent to form a multi-phase aqueous composition.

[0143] The amount of hydrophobic therapeutic agent included in thepharmaceutical compositions of the present invention can be any amountdesired by the formulator, up to the maximum amount that can besolubilized or suspended in a given carrier system. In general, theamount of hydrophobic therapeutic agent will be about 0.1% to about 60%by weight, based on the total weight of the pharmaceutical composition.In another aspect of the invention, described below, excess hydrophobictherapeutic agent can also be added, in a multi-phase dispersion.

[0144] B. Methods of Improved Delivery

[0145] In another aspect, the present invention relates to methods ofimproving delivery of hydrophobic therapeutic agents in an animal byadministering to the animal a dosage form of the pharmaceuticalcompositions described herein. Preferably the animal is a mammal, andmore preferably, a human. It has been found that the pharmaceuticalcompositions of the present invention when administered to an animalenable the hydrophobic therapeutic agent contained therein to beabsorbed more rapidly than in conventional pharmaceutical compositions.Thus, in this aspect the invention relates to a method of increasing therate of and/or extent of bioabsorption of a hydrophobic therapeuticagent by administering the hydrophobic therapeutic agent to an animal inthe pharmaceutical compositions described herein.

[0146] C. Characteristics of the Pharmaceutical Compositions

[0147] The dispersions formed upon dilution of the pharmaceuticalcompositions of the present invention have the followingcharacteristics:

[0148] Rapid formation: upon dilution with an aqueous solution, thecarrier forms a clear dispersion very rapidly; i.e., the cleardispersion appears to form instantaneously.

[0149] Optical clarity: the dispersions are essentially optically clearto the naked eye, and show no readily observable signs of heterogeneity,such as turbidity or cloudiness. More quantitatively, dispersions of thepharmaceutical compositions of the present invention show a mono-modaldistribution of very small particles sizes, typically 20 nm or less inaverage diameter; absorbances of less than about 0.3, typically lessthan about 0.1, at 10× dilution; and absorbances of less than about 0.1,typically less than about 0.01, at 100× dilution, as described morefully in the Examples herein. In the multi-phase embodiment of thecompositions described herein, it should be appreciated that the opticalclarity of the aqueous carrier dispersion phase will be obscured by thedispersed particulate non-solubilized hydrophobic therapeutic agent.

[0150] Robustness to dilution: the dispersions are surprisingly stableto dilution in aqueous solution, including aqueous solutions simulatingphysiological fluids such as enzyme-free simulated gastric fluid (SGF)and enzyme-free simulated intestinal fluid (SIF). The hydrophobictherapeutic agent remains solubilized for at least the period of timerelevant for absorption.

[0151] Triglyceride-free: It is a particular feature of the presentinvention that the pharmaceutical compositions are substantiallytriglyceride-free. The term “triglyceride” as used herein means glyceroltriesters of C₆ to about C₂₅ fatty acids. Unlike conventionalcompositions such as oil-based solutions, emulsions, and microemulsions,which rely on the solubilizing power of triglycerides, the presentcompositions surprisingly solubilize hydrophobic therapeutic agentsusing combinations of substantially triglyceride-free surfactants.

[0152] As used herein, the term “substantially triglyceride-free” meanscompositions which contain triglycerides, if at all, only as minorcomponents or impurities in surfactant mixtures. It is well known in theart that commercially available surfactants often are complex mixturesof compounds. For example, one preferred surfactant is Capmul® GMO-K, awidely-used blend of glyceryl mono- and dioleates. Due to difficultiesin separating complex product mixtures, however, a typical lot ofCapmul® GMO-K, as reported by the manufacturer's certificate ofanalysis, contains the following distribution of glyceryl esters, inpercent by weight based on the total weight of glyceryl esters: Palmiticacid 3.3% Stearic acid 4.0% Oleic acid 81.0%  Linoleic acid 9.7%Linolenic acid 0.3%

[0153] In addition, the surfactant mixture in the particular lotreported contains 0.10% water and 0.95% free, unesterified glycerol.These specific percentages are expected to vary, lot-by-lot, as well,and it is expected that commercial surfactant products will generallypossess similar variability, regardless of the specific major componentand the specific manufacturer. Thus, the present invention does notinclude surfactants which contain triglycerides as an intendedcomponent. Indeed, such surfactants are not common, since triglyceridesthemselves have no surfactant properties. However, it should beappreciated that the present invention does not exclude the use ofsurfactant products which contain small amounts of triglycerides asimpurities or as unreacted starting material. It is expected thatcommercial mixtures suitable for use in the present invention maycontain as much as 5% triglycerides by weight as unintended components.Thus, “substantially triglyceride-free” should be understood as meaningfree of added triglycerides, and containing less than 5%, preferablyessentially 0%, triglyceride impurities.

[0154] Without wishing to be bound by theory, it is believed that theobserved properties of the clear, aqueous dispersions formed by thecompositions of the present invention are consistent with, and bestexplained by, the formation of mixed micelles of the hydrophobic andhydrophilic surfactants, with the hydrophobic therapeutic agentsolubilized by the micelles. It should be emphasized that thesedispersions are characterized by the properties described herein,regardless of the precise microscopic physical form of the dispersedparticles. Nevertheless, in order to more fully explain the invention,and to illustrate its unexpected and important advantages, the followingdiscussion is offered in terms consistent with the theoreticalprinciples believed to be correct.

[0155] It is believed that the hydrophobic and hydrophilic surfactantsform mixed micelles in aqueous solution. In this model, each micelle iscomposed of molecules (or ions) of both the hydrophilic and hydrophobicsurfactants. Depending upon the detailed three-dimensional structure ofthe hydrophobic therapeutic agent, its distribution of polar moieties,if any, its polarizability in local regions, and other molecule-specificand complex factors, the hydrophobic therapeutic agent may bedistributed in any part of the micelle, such as near the outer, morehydrophilic region, near the inner, more hydrophobic region, or atvarious points in between. Further, it is known that micelles exist indynamic equilibrium with their component molecules, and it is expectedthat this equilibrium will include dynamic redistribution of thehydrophobic therapeutic agent.

[0156] As discussed above, triglyceride-containing formulations sufferthe disadvantage that bioabsorption of the hydrophobic therapeuticagents contained therein is dependent upon enzymatic degradation(lipolysis) of the triglyceride components. The pharmaceuticalcompositions of the present invention, however, are substantially freeof triglycerides, and thus do not depend upon lipolysis to enablerelease of the hydrophobic therapeutic agent for bioabsorption. Thehydrophobic therapeutic agent is in a dynamic equilibrium between thefree compound in solution and the solubilized compound, thus promotingrapid release.

[0157] The unique pharmaceutical compositions of the present inventionpresent a number of significant and unexpected advantages, including:

[0158] Efficient transport: The particle sizes in the aqueousdispersions of the present invention are much smaller, typically lessthan 20 nm, than the larger particles characteristic of vesicular,emulsion or microemulsion phases, and the particle size distribution ismono-modal and narrow. This reduced and more uniform size enables moreefficient drug transport through the intestinal aqueous boundary layer,and through the absorptive brush border membrane. More efficienttransport to absorptive sites leads to improved and more consistentabsorption of hydrophobic therapeutic agents.

[0159] Non-dependence on lipolysis: The lack of triglyceride componentsprovides pharmaceutical compositions not dependent upon lipolysis, andupon the many poorly characterized factors which affect the rate andextent of lipolysis, for effective presentation of a hydrophobictherapeutic agent to an absorptive site. Such factors include thepresence of composition components which may inhibit lipolysis; patientconditions which limit production of lipase, such as pancreatic lipasesecretory diseases; and dependence of lipolysis on stomach pH,endogenous calcium concentration, and presence of co-lipase or otherdigestion enzymes. The lack of lipolysis dependence further providestransport which does not suffer from any lag time between administrationand absorption caused by the lipolysis process, enabling a more rapidonset of therapeutic action and better bioperformance characteristics.In addition, pharmaceutical compositions of the present invention canmake use of hydrophilic surfactants which might otherwise be avoided orlimited due to their potential lipolysis inhibiting effects.

[0160] Non-dependence on bile and meal fat contents: Due to the highersolubilization potential over bile salt micelles, the presentcompositions are less dependent on endogenous bile and bile relatedpatient disease states, and meal fat contents. These advantages overcomemeal-dependent absorption problems caused by poor patient compliancewith meal-dosage restrictions.

[0161] Superior solubilization: The surfactant combinations used incompositions of the present invention enable superior loading capacityover conventional micelle formulations. In addition, the particularcombination of surfactants used can be optimized for a specifichydrophobic therapeutic agent to more closely match the polaritydistribution of the therapeutic agent, resulting in still furtherenhanced solubilization.

[0162] Faster dissolution and release: Due to the robustness ofcompositions of the present invention to dilution, the hydrophobictherapeutic agents remain solubilized and thus do not suffer problems ofprecipitation of the therapeutic agent in the time frame relevant forabsorption. In addition, the therapeutic agent is presented in smallparticle carriers, and is not limited in dilution rate by entrapment inemulsion carriers. These factors avoid liabilities associated with thepoor partitioning of lipid solubilized drug in to the aqueous phase,such as large emulsion droplet surface area, and high interfacialtransfer resistance, and enable rapid completion of the criticalpartitioning step.

[0163] Consistent performance: Aqueous dispersions of the presentinvention are thermodynamically stable for the time period relevant forabsorption, and can be more predictably reproduced, thereby limitingvariability in bioavailability—a particularly important advantage fortherapeutic agents with a narrow therapeutic index.

[0164] Efficient release: The compositions of the present invention aredesigned with components that help to keep the hydrophobic therapeuticagent solubilized for transport to the absorption site, but readilyavailable for absorption, thus providing a more efficient transport andrelease.

[0165] Less prone to gastric emptying delays: Unliketriglyceride-containing formulations, the present compositions are lessprone to gastric emptying delays, resulting in faster absorption.Further, the particles in dispersions of the present invention are lessprone to unwanted retention in the gastro-intestinal tract.

[0166] Small size: Because of the small particle size in aqueousdispersion, the pharmaceutical compositions of the present inventionallow for faster transport of the hydrophobic therapeutic agent throughthe aqueous boundary layer.

[0167] These and other advantages of the present invention, as well asaspects of preferred embodiments, are illustrated more fully in theExamples which follow.

EXAMPLES Example 1

[0168] Preparation of Compositions

[0169] A simple pre-concentrate of a hydrophobic surfactant and ahydrophilic surfactant is prepared as follows. Predetermined weighedamounts of hydrophilic and hydrophobic surfactants are stirred togetherto form a homogeneous mixture. For surfactant combinations that arepoorly miscible, the mixture can be gently heated to aid in formation ofthe homogeneous mixture. A chosen hydrophobic therapeutic agent in apredetermined amount is added and stirred until solubilized. Optionally,solubilizers or additives are included by simple mixing.

[0170] To form an aqueous dispersion of the pre-concentrate, apredetermined amount of purified water, buffer solution, or aqueoussimulated physiological solution, is added to the pre-concentrate, andthe resultant mixture is stirred to form a clear, aqueous dispersion.

Example 2

[0171] Surfactant Combinations Giving Clear Aqueous Dispersions

[0172] Surfactant mixtures giving clear, aqueous dispersions wereprepared according to the method of Example 1. Seven hydrophilicsurfactants and sixteen hydrophobic surfactants were used to produceapproximately one hundred clear aqueous dispersions suitable for use inthe present invention. For simplicity, no hydrophobic therapeutic agentwas included in these compositions, since it is believed that thepresence of the hydrophobic therapeutic agent does not substantiallyaffect the clear, aqueous nature of composition. For the same reason,these compositions were free of additional solubilizers and otheradditives.

[0173] Multiple solutions were prepared for each surfactant combination,to determine the approximate maximum amount of hydrophobic therapeuticagent giving a clear aqueous dispersion with a given amount ofhydrophilic therapeutic agent. Thus, for each gram of the hydrophilicsurfactant, a predetermined amount of hydrophobic agent was used toprepare a 10× aqueous dispersion. If the dispersion appeared to beoptically clear, a new dispersion was prepared according to Example 1,using a larger amount of hydrophobic surfactant. Similarly, if thedispersion appeared to be cloudy, a new dispersion was prepared using asmaller amount of hydrophobic surfactant. The results are shown in Table19. TABLE 19 Surfactant Combinations Giving Clear DispersionsHydrophilic Surfactant PEG-35 PEG-40H PEG-60 PEG-8 PEG-25 Castor OilCastor Oil Polysorbate Polysorbate Corn Oil Capric/ Glyceryl Hydrophobic(Incrocas (Cremophor -20 80 (Crovol M- Caprylic trioleate Surfactant 35)RH-40) (Tween 20) (Tween 80) 70) (Labrasol) (Tagat TO)Glyceryl/Propylene 20 20 20 8 15 25 10 Glycol Oleate (Arlacel 186)Glyceryl Oleate 15 40 10 12 10 35 10 (Peceol) Acetylated 80 80 20 15 1010 10 Monoglycerides (Myvacet 9-45) PEG-6 Corn Oil 50 95 10 10 20 10 10(Labrafil M2125CS) Sorbitan Monooleate 25 65 5 5 20 15 10 (Span 80)Sorbitan Monolaurate 30 20 20 10 15 30 10 (Arlacel 20) Polyglyceryloleate 10 5 35 10 10 35 10 (Plurol Oleique CC497) Propylene GlycolLaurate 10 55 35 20 15 35 10 (Lauroglycol FCC) Glyceryl Caprylate/ 10 5020 25 25 20 10 Caprate (Capmul MCM) PEG-20 Corn Oil 35 40 40 25 30 90 10(Crovol M-40) PEG-20 Almond Oil 30 35 40 25 30 90 10 (Crovol A-40)Mono/diglycerides of 50 50 60 25 25 30 10 Caprylic Acid (Imwitor 988)PEG-4-lauryl ether 40 45 95 70 * 90 10 (Brij 30) PEG-3-oleyl ether 20 3025 20 20 25 10 (Volpo 3) Glyceryl mono/dioleate * 10 * * 10 25 10(Capmul GMO-K) Ethyl Oleate 40 60 10 10 60 10 10 (Crodamol EO)

[0174] Each entry in the Table represents the approximate maximum numberof grams of hydrophobic surfactant per 100 g of hydrophilic surfactantgiving acceptable optical clarity. The numbers in the Table areillustrative only, and it is expected that further optimization of thesurfactant systems with solubilizers, co-surfactants, and otheradditives will give still higher numbers.

Example 3

[0175] Compositions Containing Solubilizers

[0176] The procedure of Example 2 was repeated for compositionscontaining PEG-40 hydrogenated castor oil (Cremophor RH 40) as thehydrophilic surfactant, with eight different hydrophobic surfactants,and four different solubilizers, to study the effect of solubilizer onthe relative amounts of hydrophobic and hydrophilic surfactants givingclear aqueous dispersions. In each case, the amount of solubilizer washeld constant at 20% by weight, based on the total weight of the twosurfactants. The results are shown in Table 20. As in Example 2, thenumbers in the Table represent the approximate maximum number of gramsof hydrophobic surfactant per 100 g of hydrophilic surfactant giving aclear aqueous dispersion. For convenience, the corresponding entriesfrom Table 19 (with no solubilizer present) are reproduced in Table 20in the column labeled “none.” TABLE 20 Effect of Solubilizer onHydrophobic Surfactant Amounts Hydrophilic Surfactant (Cremophor RH40) +20% Solubilizer PEG- Glyco- Hydrophobic Surfactant (None) TriacetinEthanol 400 furol Glyceryl/Propylene 20 28 25 25 25 Glycol Oleate(Arlacel 186) Glyceryl Oleate 40 40 42 40 44 (Peceol) SorbitanMonooleate 65 40 40 25 30 (Span 80) Sorbitan Monolaurate 20 65 * * 65(Span 20) PEG-6 Corn Oil 95 95 * 95 * (Labrafil M2125CS) Acetylated 8080 80 80 80 Monoglyceride (Myvacet 9-45) Ethyl Oleate 60 60 60 * 60(Crodamol EO) Mono/diglycerides of 50 80 * * 75 Caprylic Acid (Imwitor988)

[0177] As is clear from the data in the Table, the effect of addedsolubilizer on the relative amount of hydrophobic surfactant that can beused varies considerably. For some surfactant combinations, the addedsolubilizer has a dramatic effect on the amount of hydrophobicsurfactant (e.g., Span 20, Imwitor 988). In other systems, the effect ismoderate (Arlacel 186, Peceol) or negligible (Crodamol EO, Myvacet9-45). In the one case of Span 80, the presence of the solubilizeractually decreases the amount of hydrophobic surfactant that can beused.

Example 4

[0178] Compositions Containing Solubilizers

[0179] Example 3 was repeated, this time choosing a single hydrophobicsurfactant (Arlacel 186) and three different hydrophilic surfactants,with addition of either ethanol or triacetin (20% by weight, based onthe total weight of the two surfactants). The results are shown in Table21. The corresponding entry from Table 19 (with no solubilizer present)is included in Table 21 for reference. TABLE 21 Effect of Solubilizer onHydrophobic Surfactant Amounts Hydrophobic Surfactant (Arlacel 186) +Hydrophilic 20% Solubilizer Surfactant (None) Ethanol Triacetin PEG-60Corn Oil 15 20 20 (Crovol M-70) PEG-35 Castor Oil 20 25 25 (Incrocas 35)Polysorbate 20 20 25 25 (Tween 20)

[0180] In each case, a moderate increase (20%) in the relative amount ofhydrophobic surfactant was observed.

Example 5

[0181] Effect of Solubilizer Concentration

[0182] The procedure of Example 3 was repeated, with the followingdifferences. A single hydrophilic surfactant (Cremophor RH-40) andhydrophobic surfactant (Arlacel 186) were chosen, to examine the effectof increased solubilizer concentration. For each of the foursolubilizers tested at 20% concentrations in Example 3 (Table 20) plusan additional solubilizer (propylene glycol), compositions were testedat a solubilizer concentration of 50% by weight, based on the totalweight of the surfactant pair. As in each of the previous examples, thenumbers in Table 22 represent the maximum hydrophobic surfactantconcentration giving a clear aqueous dispersion. Note that the “0”column in Table 22 reproduces the numbers shown in Table 19 (nosolubilizer), and the “20%” column reproduces the numbers in Table 20,with the value for propylene glycol also supplied. TABLE 22 Effect ofSolubilizer Concentration on Hydrophobic Surfactant Amounts* WeightPercent of Solubilizer Solubilizer 0 20 50 PEG-400 20 25 25 PropyleneGlycol 20 28 30 Triacetin 20 28 25 Ethanol 20 25 30 Glycofurol 20 25 30

[0183] As the Table shows, increasing the amount of solubilizer has asmall to moderate effect on the amount of hydrophobic surfactant thatcan be present in a clear aqueous dispersion. It should be appreciatedthat the data equivalently show that very large amounts of solubilizercan be used, without detrimental effect on the ability of the surfactantsystem to form a clear, aqueous dispersion.

Example 6

[0184] Effect of High Solubilizer Concentration and Solubilizer Mixtures

[0185] Example 5 was repeated, using the same surfactant pair, but withan 80% concentration of solubilizer, based on the total weight of thesurfactants. The 80% solubilizer was either PEG-400, or a mixture ofPEG-400 and one of three alcohols or polyols. The results are shown inTable 23, with the numbers in the Table having the same meaning as inthe previous Examples. TABLE 23 Large Solubilizer Concentrations andSolubilizer Mixtures* 60% 60% 60% PEG-400 + PEG-400 + (no 80% PEG-400 +20% Propylene 20% solubilizer) PEG-400 20% Glycerol Glycol Isopropanol20 25 25 25 25

[0186] It is clear from the data in the Table that very highconcentrations of solubilizers, as well as mixtures of solubilizers, canbe used effectively in the clear aqueous dispersions of the presentinvention.

Examples 7-12

[0187] Average Particle Size

[0188] In order to more quantitatively characterize the clear aqueousdispersions of the present invention, particle sizes were measured forseveral compositions of the present invention. For simplicity, themeasurement were made for the dispersed carrier, in the absence of ahydrophobic therapeutic agent. In this Example, formulations wereprepared as in Example 1, and diluted to form 10× or 100× aqueousdispersions. Each of the resulting dispersions was observed to beoptically clear to the naked eye. Average particle sizes were measuredwith a Nicomp Particle Size Analyzer (Particle Size Systems, Inc., SantaBarbara, Calif.). The results of these measurements are shown in Table24. TABLE 24 Average Particle Size Ex- Particle am- Sur- Size plefactant Dilu- Observa- (nm) ± No. Formula Ratio* tion tion S.D.** 7Tween 80 520 mg 9.6 100X very clear  6.5 ± 1.1 Lauroglycol 50 mgsolution FCC 8 Tween 80 500 mg 15  10X very clear  8.1 ± 1.6 Capmul 73mg solution MCM 9 Cremophor 530 mg 28 100X clear 12.4 ± 3.0 RH-40 150 mgsolution Peceol 10 Cremophor 500 mg 2.0 100X clear 14.7 ± 3.0 RH-40 10mg solution Plurol Oleique CC497 11 Cremophor 550 mg 36 100X clear 14.3± 2.5 RH-40 200 mg solution Lauroglycol FCC 12 Cremophor 500 mg 40 100Xclear 12.6 ± 2.9 RH-40 200 mg solution Capmul MCM

[0189] As the data show, the compositions of the present inventionproduce clear, aqueous dispersions, with no visible cloudiness. Theparticle size distribution shows very small particles, with averagediameters of from about 6 to about 15 nm. The distribution ismono-modal, with a standard deviation of approximately 20%, indicating ahighly uniform distribution of very small particles. This particle sizedistribution is consistent with a solution of particles of micellarstructure, although the invention is not limited by any particulartheoretical framework.

Comparative Examples C1-C5

[0190] Optical Clarity and Particle Sizes of Compositions Not FormingClear Aqueous Dispersions

[0191] For comparison to the clear aqueous dispersions of the presentinvention, several compositions were prepared having hydrophobicsurfactant concentrations higher than those suitable for forming clearaqueous dispersions. These compositions were prepared by weighing thecomponents and mixing well, with gentle warming. The compositions werethen diluted 10× to form dispersions, and these dispersions weresubjected to the particle size measurements as described in Example 7.The results are shown in Table 25. For direct comparison with thecompositions of the present invention, Examples 7, 9, 10, 11 and 12 areshown next to the corresponding comparative compositions. TABLE 25Optical Clarity and Particle Size Example Surfactant Particle Size(nm)** No. Surfactants Ratio* Observation Mean 1 Mean 2 C1 Tween 80 67milky 26.6 209 Lauroglycol solution FCC 7 Tween 80 9.6 very clear 6.5 —Lauroglycol solution FCC C2 Cremophor 67 milky 25 116 RH-40 solutionPeceol 9 Cremophor 28 clear 8.1 — RH-40 solution Peceol C3 Cremophor 67milky 16.5 102 RH-40 solution Plurol Oleique CC497 10 Cremophor 2.0clear 12.4 — RH-40 solution Plurol Oleique CC497 C4 Cremophor 69 hazy17.1 45.3 RH-40 solution Lauroglycol FCC 11 Cremophor 36 clear 14.3RH-40 solution Lauroglycol FCC C5 Cremophor 67 milky 11.6 176 RH-40solution Capmul MCM 12 Cremophor 40 clear 12.6 — RH-40 solution CapmulMCM

[0192] In addition to the compositions shown in the Table, compositionscontaining Tween 80 and Plurol Oleique CC497, Tween 80 and Peceol, andTween 80 and Capmul MCM were prepared at a surfactant ratio of 67 ghydrophobic surfactant per 100 g hydrophilic surfactant. Particle sizeswere not measured for these compositions, but each was observed to forma milky or hazy aqueous dispersion.

[0193] As the data show, compositions having excessive amounts ofhydrophobic surfactant form milky or hazy solutions, whereas those ofthe present invention form clear solutions. In addition, the particlesize distributions of the milky solutions are bimodal, in contrast tothe mono-modal solutions of the corresponding clear solutions. Thesebimodal particle size distributions show a first mode having a smallmean particle size of about 12 to about 27 nm, and a second mode havingparticle sizes of up to more than 200 nm. Thus, compositions havingexcessive hydrophobic surfactant are heterogeneous (multi-phasic),non-clear dispersions, having a complex bimodal distribution ofparticles of two distinct size ranges. In contrast, compositions of thepresent invention are homogeneous (single phase), clear dispersion,having a mono-modal distribution of very small particle sizes.

Examples 13-42

[0194] Spectroscopic Characterization of Optical Clarity

[0195] The optical clarity of aqueous dispersions of the presentinvention was measured spectroscopically. Compositions were preparedaccording to Example 1, and diluted to 10× and 100× solutions. Thespecific compositions measured also include a solubilizer, to furtherillustrate preferred aspects of the invention. In addition, several ofthe compositions illustrate compositions according to the presentinvention wherein either the hydrophilic surfactant (Examples 20 and 27)or the hydrophobic surfactant (Examples 41 and 42) itself is a mixtureof surfactants.

[0196] The absorbance of each solution was measured at 400.2 nm, using apurified water standard, and the results are shown in Table 26. TABLE 26Spectroscopic Characterization of Optical Clarity Example Absorbance(400.2 nm) No. Formulation 10X 100X 13 Cremophor RH-40 430 mg 0.4070.099 Myvacet 9-45 310 mg Ethyl Alcohol 210 mg 14 Cremophor RH-40 610 mg0.299 0.055 Peceol 160 mg Ethyl Alcohol 200 mg 15 Cremophor RH-40 540 mg0.655 0.076 Span 80 260 mg Triacetin 220 mg 16 Incrocas 35 470 mg 0.1580.038 Myvacet 9-45 250 mg Ethyl Alcohol 220 mg 17 Incrocas 35 510 mg0.064 0.009 Imwitor 988 220 mg Triacetin 200 mg 18 Tween 20 570 mg 0.0310.003 Lauroglycol FCC 140 mg Glycofurol 220 mg 19 Crovol M70 610 mg0.049 0.006 Crovol M40 120 mg Ethyl Alcohol 200 mg 20 Cremophor RH-40250 mg 0.028 0.008 Labrasol 250 mg Capmul GMO-K 110 mg Triacetin 100 mg21 Cremophor RH-40 220 mg 0.114 0.018 Lauroglycol FCC 200 mg EthylAlcohol 75 mg 22 Tween 80 170 mg 0.050 0.008 Capmul MCM 30 mg EthylAlcohol 38 mg 23 Cremophor RH-40 550 mg 0.029 0.006 Capmul MCM 80 mgEthyl Alcohol 53 mg 24 Cremophor RH-40 230 mg 0.187 0.020 Peceol 70 mgEthyl Alcohol 54 mg 25 Cremophor RH-40 500 mg 0.028 0.005 Plurol Oleique10 mg CC497 11 mg Ethyl Alcohol 26 Tween 80 180 mg 0.036 0.003Lauroglycol FCC 20 mg Ethyl Alcohol 37 mg 27 Tween 80 420 mg 0.036 0.009Labrasol 330 mg Arlacel 186 54 mg Ethyl Alcohol 140 mg 28 Tagat O2 500mg 0.077 0.005 PGMG-03 50 mg Ethyl Alcohol 100 mg 29 Incrocas 35 250 mg0.053 0.005 Gelucire 44/14 150 mg Triacetin 94 mg 30 Cremophor RH-40 270mg 0.232 0.047 Labrafil 170 mg Ethyl Alcohol 100 mg 31 Crovol M-70 380mg 0.064 0.011 Labrafil 50 mg Triacetin 100 mg 32 Cremophor RH-40 300 mg0.163 0.034 Peceol 110 mg Triacetin 110 mg 33 Tween 20 340 mg 0.0380.005 Lauroglycol FCC 110 mg Glycofurol 100 mg 34 Incrocas-35 310 mg0.101 0.020 Labrafil 110 mg Ethyl Alcohol 100 mg 35 Cremophor RH-40 300mg 0.908 0.114 Span 80 130 mg Triacetin 100 mg 36 Cremophor RH-40 510 mg0.039 0.008 Arlacel 186 58 mg Propylene Glycol 55 mg 37 Cremophor RH-40510 mg 0.440 0.100 Peceol 140 mg Propylene Glycol 58 mg 38 CremophorRH-40 500 mg 0.411 0.107 Labrafil M2125CS 400 mg Propylene Glycol 88 mg39 Cremophor RH-40 550 mg 0.715 0.106 Span 80 220 mg Propylene Glycol 78mg 40 Cremophor RH-40 500 mg 0.547 0.147 Crodamol 280 mg PropyleneGlycol 100 mg 41 Cremophor RH-40 550 mg 0.419 0.055 Labrafil M2125CS 340mg Span 80 200 mg Ethyl Alcohol 110 mg 42 Cremophor RH-40 500 mg 0.2930.260 Labrafil M2125CS 270 mg Crovol M-40 280 mg Ethyl Alcohol 100 mg

[0197] Ideally, a clear aqueous dispersion should have a very hightransmittance, indicating little scattering of light by large particles.Absorbance and transmittance are related by the simple expression

A=−log T

[0198] where A is absorbance, and T is the transmittance expressed as adecimal. Thus, preferred solutions of the present invention will havesmall absorbances. As noted above, in the absence of true absorption(due to chromophores in solution), suitable clear aqueous dispersions ofthe present invention should have an absorbance at 10× dilution of lessthan about 0.3.

[0199] The data in Table 26 show 30 solutions, 22 of which haveabsorbances less than about 0.3 at 10× dilution. Of these solutions, 3have absorbances between 0.2 and 0.3, 5 have absorbances between 0.1 and0.2, and 14 have absorbances less than 0.1. Thus, for the majority ofthe solutions, absorbance provides an adequate measure of opticalclarity.

[0200] Solutions having absorbances greater than 0.3 may still besuitable for use in the present invention, as these are observed to haveacceptable optical clarity by visual examination. For these relativelyhigh absorbance solutions, this simple spectroscopic measure of opticalclarity is inadequate, and other methods are more well-suited toassessing optical clarity, such as visual observation and particle size.As an example, Example 37, which shows an absorbance of 0.440, has asurfactant ratio of 27, well below the value of 40 shown in Table 19,and is observed to be a clear solution. This same composition, withoutthe additional solubilizer, is shown in Example 9 at a surfactant ratioof 28 to have a mono-modal, narrow particle size distribution, at anaverage particle size of 12.4 nm. It should be appreciated that directparticle size measurement and absorbance measurement are different waysof assessing optical clarity, and provide alternative criteria forquantifying clarity. However, it is believed that the simple,qualitative visual observation of optical clarity is a sufficientmeasure of suitable clarity for use in the present invention,particularly so since compositions outside the scope of the inventionshow marked and unmistakable cloudiness without recourse to quantitativemeasurement (See, e.g., Comparative Example 1).

Comparative Examples C6-C12

[0201] Spectroscopic Characterization of Compositions Not Forming ClearAqueous Dispersions

[0202] For comparison to the clear aqueous dispersions of the presentinvention, compositions observed to be milky or cloudy werecharacterized by absorption, as in Examples 13-42. Where available,results for comparable solutions from Examples 13-42 are reproduced forcomparison. In such cases, where a given surfactant combination ispresented in Examples 13-42 more than once (with different solubilizerconcentrations), the composition having the lowest solubilizerconcentration is chosen, to facilitate more direct comparison. Theresults are shown in Table 27. TABLE 27 Comparative SpectroscopicCharacterization Example Absorbance (400.2 nm) No. Formulation 10X 100XC6 Tween 80 100 mg 2.938 2.827 Lauroglycol FCC 67 mg 26 Tween 80 180 mg0.036 0.003 Lauroglycol FCC 20 mg Ethyl Alcohol 37 mg C7 Tween 80 100 mg0.980 0.932 Capmul MCM 67 mg 22 Tween 80 170 mg 0.050 0.008 Capmul MCM30 mg Ethyl Alcohol 38 mg C8 Cremophor RH-40 100 mg 2.886 1.595 PlurolOleique CC497 67 mg 25 Cremophor RH-40 500 mg 0.028 0.005 Plurol OleiqueCC497 10 mg Ethyl Alcohol 11 mg C9 Cremophor RH-40 100 mg 2.892 1.507Peceol 67 mg 24 Cremophor RH-40 230 mg 0.187 0.020 Peceol 70 mg EthylAlcohol 54 mg C10 Cremophor RH-40 100 mg 1.721 0.491 Capmul MCM 67 mg 23Cremophor RH-40 550 mg 0.029 0.006 Capmul MCM 80 mg Ethyl Alcohol 53 mgC11 Tween 80 100 mg 1.585 1.357 Plurol Oleique CC497 67 mg C12 Tween 80100 mg 2.849 2.721 Peceol 67 mg

[0203] The data in the Table demonstrate that the clear aqueousdispersions of the present invention show very different absorptivebehavior from compositions having excessive hydrophobic surfactantconcentrations, having apparent absorbances (through scattering losses)lower by at least a factor of ten, and in some cases by a factor of morethan one hundred.

Examples 43 and 44

[0204] Solubility of a Polyfunctional Hydrophobic Therapeutic Agent

[0205] The enhanced solubility of a typical polyfunctional hydrophobictherapeutic agent, cyclosporin, in the pharmaceutical compositions ofthe present invention was measured using a conventional “shake flask”method. Compositions were prepared and diluted to 10× and 100× as inExample 1, without including the therapeutic agent. The solutions werethen provided with an excess of cyclosporin, and agitated to allow thecyclosporin to achieve an equilibrium partitioning between thesolubilized phase and the non-solubilized dispersion phase.Concentration of the solubilized cyclosporin was then determined usingstandard HPLC techniques, optimized for the quantitative detection ofcyclosporin. The results are shown in Table 28. TABLE 28 Solubility ofCyclosporin in Clear Aqueous Dispersions Ex- ample Solubility (μg/mL)No. Carrier Composition 10X Dilution 100X Dilution 43 Cremophor RH-40430 mg 13,205 1,008 Myvacet 9-45 321 mg Ethyl Alcohol 210 mg 44Cremophor RH-40 540 mg 11,945 1,127 Span 80 260 mg Triacetin 220 mg

[0206] This Example demonstrates the dramatically enhanced solubility ofa hydrophobic therapeutic agent in the pharmaceutical compositions ofthe present invention.

Comparative Examples C13-C16

[0207] Solubility of a Polyfunctional Hydrophobic Therapeutic Agent

[0208] For comparison, the solubility experiment of Examples 43-44 wasperformed on four standard aqueous solutions. The first comparisonsolution was purified water with no additives. Next, a standardsimulated intestinal fluid (SIF) was used, to simulate the in vivoconditions to be encountered by the hydrophobic therapeutic agent. Athird solution was prepared with simulated intestinal fluid, plus anadditional aliquot of 20 mM sodium taurocholate (a bile salt); thissolution is designated SIFB in Table 29. Finally, a fourth solution wasprepared with simulated intestinal fluid, 20 mM sodium taurocholate, and5 mM lecithin; this solution is designated SIFBL. The 20 mM bile saltand 5 mM lecithin concentrations are believed to be representative ofthe average concentration of these compounds encountered in thegastrointestinal tract. As in the previous Examples, these comparisonsolutions were equilibrated with cyclosporin using the shake flaskmethod, and analyzed by HPLC. The results of these measurements arepresented in Table 29. TABLE 29 Solubility of Cyclosporin in AqueousSolutions Example No. Solution Solubility (μg/mL) C13 Water 6 C14 SIF 6C15 SIFB 49 C16 SIFBL 414 43-44 (average at 10X) present invention12,575

[0209] As the Table indicates, the solubility of the polyfunctionalhydrophobic therapeutic agent in the compositions of the presentinvention is far greater than its solubility in aqueous andgastrointestinal aqueous solutions.

Examples 45-49

[0210] Solubility of a Lipophilic Hydrophobic Therapeutic Agent

[0211] The enhanced solubility of a typical lipophilic hydrophobictherapeutic agent, progesterone, in the pharmaceutical compositions ofthe present invention was measured as described in Examples 43-44. Theresults are shown in Table 30. TABLE 30 Solubility of Progesterone inClear Aqueous Dispersions Ex- ample Solubility (μg/mL) No. CarrierComposition 10X Dilution 100X Dilution 45 Cremophor RH-40 1000 mg 1100200 Arlacel 186 120 mg Propylene Glycol 110 mg 46 Cremophor RH-40 1000mg 1240 140 Peceol 240 mg Propylene Glycol 120 mg 47 Cremophor RH-401000 mg 1760 190 Labrafil M2125CS 800 mg Propylene Glycol 180 mg 48Cremophor RH-40 1000 mg 1360 160 Span 80 350 mg Propylene Glycol 140 mg49 Cremophor RH-40 1000 mg 1720 190 Crodamol EO 600 mg Propylene Glycol160 mg

[0212] This Example demonstrates the dramatically enhanced solubility ofa hydrophobic therapeutic agent in the pharmaceutical compositions ofthe present invention.

Comparative Examples C17-C20

[0213] Solubility of a Lipophilic Hydrophobic Therapeutic Agent

[0214] For comparison, the solubility experiment of Comparative ExamplesC13-C16 was repeated, using progesterone instead of cyclosporin. Theresults of these measurements are presented in Table 31. TABLE 31Solubility of Progesterone in Aqueous Solutions Example No. SolutionSolubility (μg/mL) C17 Water   6 C18 SIF  7-10 C19 SIFB 32-40 C20 SIFBL 80 45-49 (average at 10X) present invention 1436

[0215] As the Table indicates, the solubility of the lipophilichydrophobic therapeutic agent in the compositions of the presentinvention is far greater than its solubility in aqueous andgastrointestinal aqueous solutions.

Examples 50-57

[0216] Aqueous Dilution Stability of Compositions Containing aPolyfunctional Hydrophobic Therapeutic Agent

[0217] Compositions according to the present invention were prepared,with a typical polyfunctional hydrophobic therapeutic agent,cyclosporin, as the therapeutic agent. The compositions were prepared asdescribed in Example 1, except that the ingredients were added in theorder listed in Table 32. The pre-concentrates were diluted 100× withpurified water, and a visual observation was made immediately afterdilution. The solutions were then allowed to stand 6 hours to assessdilution stability, then the cyclosporin concentration in solution wasmeasured, using a drug-specific HPLC assay. The results are shown inTable 32. TABLE 32 Dilution Stability of Polyfunctional TherapeuticAgents Cyclosporin Example Concen- No. Composition Observation tration*50 Cremophor RH-40 430 mg clear solution 121 Myvacet 9-45 310 mg EthylAlcohol 210 mg Cyclosporin  99 mg 51 Cremophor RH-40 610 mg clearsolution 99  Peceol 160 mg Ethyl Alcohol 200 mg Cyclosporin 100 mg 52Cremophor RH-40 540 mg clear solution 114 Span 80 260 mg Triacetin 220mg Cyclosporin  97 mg 53 Incrocas 35 470 mg clear solution 96  Myvacet9-45 250 mg Ethyl Alcohol 220 mg Cyclosporin 100 mg 54 Cremophor RH-40660 mg clear solution 105 Arlacel 186 120 mg Propylene Glycol 100 mgEthanol 100 mg Cyclosporin 100 mg 55 Cremophor RH-40 550 mg clearsolution 102 Arlacel 186 120 mg Propylene Glycol 450 mg Cyclosporin 100mg 56 Cremophor RH-40 580 mg clear solution 108 Arlacel 186 120 mgPropylene Glycol 100 mg Ethanol 100 mg Cyclosporin 100 mg 57 Gelucire44/14 120 mg clear solution 108 Incrocas 35 200 mg (at 37° C.)Glycofurol 100 mg Cyclosporin 100 mg

[0218]

[0219] The data in the Table indicate that large amounts of apolyfunctional hydrophobic therapeutic agent can be solubilized in thecompositions of the present invention to produce clear, aqueousdispersions. These dispersions show no instability effects, such ashydrophobic therapeutic agent precipitation or particle agglomeration,upon standing.

Examples 58-74

[0220] Aqueous Dilution Stability of Compositions Containing aLipophilic Hydrophobic Therapeutic Agent

[0221] Compositions according to the present invention were prepared,with a typical lipophilic hydrophobic therapeutic agent, progesterone,as the therapeutic agent. The compositions were prepared and analyzed asin Examples 50-57, and the results are shown in Table 33. TABLE 33Dilution Stability of Lipophilic Therapeutic Agents Proges- teroneExample Concen- No. Composition Observation tration* 58 Cremophor RH-401000 mg very clear 99.1 Arlacel 186 120 mg solution Propylene Glycol 110mg Progesterone 48 mg 59 Cremophor RH-40 1000 mg very clear 99.3 Peceol240 mg solution Propylene Glycol 120 mg Progesterone 48 mg 60 CremophorRH-40 1000 mg very clear 100.2 Labrafil 800 mg solution Propylene Glycol180 mg Progesterone 45 mg 61 Cremophor RH-40 1000 mg very clear 97.2Span 80 350 mg solution Propylene Glycol 140 mg Progesterone 50 mg 62Cremophor RH-40 1000 mg very clear 98.4 Crodamol EO 600 mg solutionPropylene Glycol 160 mg Progesterone 48 mg 63 Cremophor RH-40 540 mgclear solution 104.4 Labrafil M2125CS 350 mg Ethyl Alcohol 200 mgProgesterone 42 mg 64 Cremophor RH-40 570 mg very slight tang 106.1Ethyl Oleate 260 mg blue color Ethyl Alcohol 200 mg solutionProgesterone 42 mg 65 Cremophor RH-40 600 mg very slight tang 104.6Peceol 210 mg blue color Triacetin 210 mg solution Progesterone 42 mg 66Cremophor RH-40 600 mg very clear 97.7 Capmul MCM 200 mg solutionTriacetin 200 mg Progesterone 44 mg 67 Cremophor RH-40 590 mg clearsolution 102.3 Span 80 270 mg Triacetin 210 mg Progesterone 41 mg 68Crovol M-70 760 mg very clear 104.6 Labrafil M2125CS 100 mg solutionTriacetin 200 mg Progesterone 43 mg 69 Tween 20 610 mg very slight tang98.0 Imwitor 988 300 mg blue color Triacetin 200 mg solutionProgesterone 45 mg 70 Tween 20 670 mg very clear 96.3 Lauroglycol FCC170 mg solution Glycofurol 200 mg Progesterone 43 mg 71 Incrocas 35 620mg very clear 99.5 Labrafil M2125CS 220 mg solution Ethyl Alcohol 200 mgProgesterone 43 mg 72 Incrocas 35 660 mg very clear 105.9 Span 20 160 mgsolution Ethyl Alcohol 210 mg Progesterone 41 mg 73 Cremophor RH-40 980mg very clear 103.7 Arlacel 186 130 mg supernatant Propylene Glycol 110mg Progesterone 110 mg 74 Cremophor RH-40 520 mg very clear 103.1Labrafil 400 mg supernatant Propylene Glycol 110 mg Progesterone 100 mg

[0222] The data in the Table indicate that a lipophilic hydrophobictherapeutic agent can be solubilized in the compositions of the presentinvention to produce clear, aqueous dispersions. These dispersions showno instability effects, such as hydrophobic therapeutic agentprecipitation or particle agglomeration, upon standing.

Example 75

[0223] Enhancement of Bioabsorption

[0224] Studies were performed to establish that the clear aqueousdispersions of the present invention facilitate an increased rate ofbioabsorption of the hydrophobic therapeutic agent contained therein.The studies used a rat model with perfused intestinal loop along withcannulation of the mesenteric vein. This unique methodology enabledassessment of the “true” absorption potential free of any systemicmetabolic interference.

[0225] A representative preconcentrate of the present inventioncontaining a cyclosporin hydrophobic therapeutic agent was used. Thecomposition had the following formulation: Cyclosporine 0.140 gCremophor RH-40 0.41 g Arlacel 186 0.29 g Sodium taurocholate 0.26 gPropylene glycol 0.46 g

[0226] For this experiment, the preconcentrate was diluted with anisotonic aqueous HEPES buffer rather than purified water. The resultantsolution was spiked with radioactive active and perfused throughisolated ileal lumen segment of known length and diameter. Loss ofradioactivity from the lumenal side and appearance of radioactivity inthe mesenteric blood from the other side was monitored as an indicatorof absorption.

Experimental Details

[0227] Young adult (275-300 g) male Sprague Dawley rats were used. Theprocedures were consistent with those reported by Winne et al., “In vivostudies of mucosal-serosal transfer in rat jejunum”,Naunyn-Schmeideberg's Arch. Pharmacol., 329, 70 (1985).

[0228] Jugular vein cannulation: the animal was anesthetized using 2%halothane in 98% oxygen via a halothane vaporizer (Vapomatic, A. M.Bickford, Inc., NY). An opening in the jugular vein was made with a 21ga needle and a jugular cannula consisting of a 4 cm segment of silastictubing connected to polyethylene tubing was inserted in the jugular veinand secured with cyanoacrylate glue. For the donor rat, approximately 20mL of blood was freshly collected in the presence of heparin (1,000units) and the collected blood was infused at a rate of 0.2 mL/minthrough the jugular vein in the experimental rat to replenish bloodsampling.

[0229] Intestine cannulation: after the animal was anesthetized, itsbody temperature was maintained at 37° C. using a heating pad. Avertical midline incision of approximately 3 cm was made through theskin to expose the small intestine. Approximately 6-10 cm segment ofileum was located. Using electro-cautery, a small incision was made atthe ends of the segment and the lumenal contents were flushed withsaline maintained at 37° C. Two 1.5 cm notched pieces of Teflon tubingwere inserted into the intestinal lumen at each incision and tightenedusing 4-0 silk. A warm isotonic buffer was passed through the intestineusing a 50-mL syringe. These Teflon cannula were used to perfuse thedrug solution through the isolated intestinal segment using a syringepump.

[0230] Mesenteric vein cannulation: the mesenteric vein draining bloodfrom the resulting isolated mesenteric cascade venules was thencannulated using a 24 ga IV catheter and secured in place using 4-0 silksutures. The cannula was then connected to a polyethylene tubing 25 cmlong where the blood was collected in a vial kept under the animallevel. Blood samples were collected continuously over 60 min. Theinfusion of blood via the jugular vein was initiated to replenish bloodloss. The animal was then killed by a lethal injection of Phenobarbitalafter completion of the experiment.

[0231] The experiment was performed twice using the compositions of thepresent invention as the drug carrier, and twice using a commercialcyclosporin microemulsion formulation for comparison (NeOral®). For eachformulation, the results of the two trials were averaged. The resultsare presented graphically in FIG. 1.

[0232]FIG. 1 shows the accumulated radioactivity (μCi/cm²μCi) inmesenteric blood as a function of time, over the course of 60 minutes,for the pharmaceutical compositions of the present invention (filledsquares) and a commercial cyclosporin formulation (filled circles). Asthe Figure shows, the bioabsorption of the hydrophobic therapeutic agentexceeds that of the commercial formulation at the earliest measurementpoint, and continues to increase relative to the commercial formulationover the course of the measurement interval. At the final measurementpoint (60 min), the bioabsorption of the hydrophobic therapeutic agentfrom the compositions of the present invention exceeds that of thecommercial formulation by nearly 100%.

[0233] The present invention may be embodied in other specific formswithout departing from its spirit or essential characteristics. Thedescribed embodiments are to be considered in all respects only asillustrative and not restrictive. The scope of the invention is,therefore, indicated by the appended claims rather than by the foregoingdescription. All changes which come within the meaning and range ofequivalency of the claims are to be embraced within their scope.

What is claimed and desired to be secured by United States LettersPatent is:
 1. A pharmaceutical composition comprising: (a) a hydrophobictherapeutic agent; and (b) a carrier,  said carrier comprising: (i) atleast one hydrophilic surfactant; and (ii) at least one hydrophobicsurfactant,  said hydrophilic and hydrophobic surfactants being presentin amounts such that upon mixing with an aqueous solution the carrierforms a clear aqueous dispersion of the hydrophilic and hydrophobicsurfactants containing the hydrophobic therapeutic agent, saidcomposition being substantially free of triglycerides.
 2. Thepharmaceutical composition of claim 1, wherein the hydrophobicsurfactant is present in an amount of less than about 200% by weight,relative to the amount of the hydrophilic surfactant.
 3. Thepharmaceutical composition of claim 2, wherein the hydrophobicsurfactant is present in an amount of less than about 100% by weight,relative to the amount of the hydrophilic surfactant.
 4. Thepharmaceutical composition of claim 3, wherein the hydrophobicsurfactant is present in an amount of less than about 60% by weight,relative to the amount of the hydrophilic surfactant.
 5. Thepharmaceutical composition of claim 1, wherein the hydrophilicsurfactant comprises at least one non-ionic hydrophilic surfactanthaving an HLB value greater than or equal to about
 10. 6. Thepharmaceutical composition of claim 1, wherein the hydrophilicsurfactant comprises at least one ionic surfactant.
 7. Thepharmaceutical composition of claim 5, which further comprises at leastone ionic surfactant.
 8. The pharmaceutical composition of claim 5,wherein the non-ionic surfactant is selected from the group consistingof alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylenealkylphenols; polyethylene glycol fatty acids esters; polyethyleneglycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acidesters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerolfatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction mixtures ofpolyols and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;sugar esters, sugar ethers; sucroglycerides; and mixtures thereof. 9.The pharmaceutical composition of claim 5, wherein the non-ionichydrophilic surfactant is selected from the group consisting ofpolyoxyethylene alkylethers; polyethylene glycol fatty acids esters;polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitanfatty acid esters; polyoxyethylene-polyoxypropylene block copolymers;polyglycerol fatty acid esters; polyoxyethylene glycerides;polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetableoils; reaction mixtures of polyols and at least one member of the groupconsisting of fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols; and mixtures thereof.
 10. Thepharmaceutical composition of claim 9, wherein the glyceride is amonoglyceride, diglyceride, triglyceride, or a mixture thereof.
 11. Thepharmaceutical composition of claim 9, wherein the reaction mixturecomprises the transesterification products of a polyol and at least onemember of the group consisting of fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols.
 12. The pharmaceuticalcomposition of claim 9, wherein the polyol is glycerol, ethylene glycol,polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or amixture thereof.
 13. The pharmaceutical composition of claim 5, whereinthe hydrophilic surfactant is PEG-10 laurate, PEG-12 laurate, PEG-20laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate,PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG400oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate,PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glycerylstearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil,PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil,PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenatedcastor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate,PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20,polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleylether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate,PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, apoloxamer, or a mixture thereof.
 14. The pharmaceutical composition ofclaim 5, wherein the hydrophilic surfactant is PEG-20 laurate, PEG-20oleate, PEG-35 castor oil, PEG-40 palm kernel oil, PEG-40 hydrogenatedcastor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, polyglyceryl-10laurate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylateglycerides, PEG-30 cholesterol, polysorbate 20, polysorbate 80, POE-9lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, PEG-24cholesterol, sucrose monostearate, sucrose monolaurate, a poloxamer, ora mixture thereof.
 15. The pharmaceutical composition of claim 5,wherein the hydrophilic surfactant is PEG-35 castor oil, PEG-40hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate,PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polysorbate 20, polysorbate 80, tocopheryl PEG-1000 succinate, PEG-24cholesterol, a poloxamer, or a mixture thereof.
 16. The pharmaceuticalcomposition of claim 6, wherein the ionic surfactant is selected fromthe group consisting of alkyl ammonium salts; bile acids and salts,analogues, and derivatives thereof; fatty acid derivatives of aminoacids, oligopeptides, and polypeptides; glyceride derivatives of aminoacids, oligopeptides, and polypeptides; acyl lactylates;mono-,diacetylated tartaric acid esters of mono-,diglycerides;succinylated monoglycerides; citric acid esters of mono-,diglycerides;alginate salts; propylene glycol alginate; lecithins and hydrogenatedlecithins; lysolecithin and hydrogenated lysolecithins;lysophospholipids and derivatives thereof; phospholipids and derivativesthereof; salts of alkylsulfates; salts of fatty acids; sodium docusate;and mixtures thereof.
 17. The pharmaceutical composition of claim 6,wherein the ionic surfactant is selected from the group consisting ofbile acids and salts, analogues, and derivatives thereof; lecithins,lysolecithin, phospholipids, lysophospholipids and derivatives thereof;salts of alkylsulfates; salts of fatty acids; sodium docusate; acyllactylates; mono-,diacetylated tartaric acid esters ofmono-,diglycerides; succinylated monoglycerides; citric acid esters ofmono-,diglycerides; and mixtures thereof.
 18. The pharmaceuticalcomposition of claim 6, wherein the ionic surfactant is selected fromthe group consisting of lecithin, lysolecithin, phosphatidylcholine,phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid,phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholate, taurocholate, glycocholate,deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate,glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate,tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyltaurocholate, caproate, caprylate, caprate, laurate, myristate,palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, laurylsulfate, teracecyl sulfate, docusate, and salts and mixtures thereof.19. The pharmaceutical composition of claim 6, wherein the ionicsurfactant is selected from the group consisting of lecithin,lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylglycerol, lysophosphatidylcholine,PEG-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholate, taurocholate, glycocholate,deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine,caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate,and salts and mixtures thereof.
 20. The pharmaceutical composition ofclaim 6, wherein the ionic surfactant is selected from the groupconsisting of lecithin, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, taurocholate, caprylate, caprate, oleate,lauryl sulfate, docusate, and salts and mixtures thereof.
 21. Thepharmaceutical composition of claim 1 wherein the hydrophobic surfactantis a compound or mixture of compounds having an HLB value less thanabout
 10. 22. The pharmaceutical composition of claim 21, wherein thehydrophobic surfactant is selected from the group consisting ofalcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acidesters; acetylated glycerol fatty acid esters; lower alcohol fatty acidsesters; polyethylene glycol fatty acids esters; polyethylene glycolglycerol fatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives ofmono/diglycerides; propylene glycol diglycerides; sorbitan fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; transesterifiedvegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers;sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylenehydrogenated vegetable oils; reaction mixtures of polyols and at leastone member of the group consisting of fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols; and mixtures thereof.23. The pharmaceutical composition of claim 21, wherein the hydrophobicsurfactant is selected from the group consisting of fatty acids; loweralcohol fatty acid esters; polyethylene glycol glycerol fatty acidesters; polypropylene glycol fatty acid esters; polyoxyethyleneglycerides; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lactic acid derivatives of mono/diglycerides; sorbitan fattyacid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylenevegetable oils; polyoxyethylene hydrogenated vegetable oils; reactionmixtures of polyols and at least one member of the group consisting offatty acids, glycerides, vegetable oils, hydrogenated vegetable oils,and sterols; and mixtures thereof.
 24. The pharmaceutical composition ofclaim 21, wherein the hydrophobic surfactant is selected from the groupconsisting of lower alcohol fatty acids esters; polypropylene glycolfatty acid esters; propylene glycol fatty acid esters; glycerol fattyacid esters; acetylated glycerol fatty acid esters; lactic acidderivatives of mono/diglycerides; sorbitan fatty acid esters;polyoxyethylene vegetable oils; and mixtures thereof.
 25. Thepharmaceutical composition of claim 21, wherein the hydrophobicsurfactant is a glycerol fatty acid ester, an acetylated glycerol fattyacid ester, or a mixture thereof.
 26. The pharmaceutical composition ofclaim 25, wherein the glycerol fatty acid ester is a monoglyceride,diglyceride, or a mixture thereof.
 27. The pharmaceutical composition ofclaim 26, wherein the fatty acid of the glycerol fatty acid ester is aC₆ to C₂₀ fatty acid or a mixture thereof.
 28. The pharmaceuticalcomposition of claim 21, wherein the hydrophobic surfactant is areaction mixture of a polyol and at least one member of the groupconsisting of fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols.
 29. The pharmaceutical composition of claim28, wherein the reaction mixture is a transesterification product of apolyol and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.30. The pharmaceutical composition of claim 28, wherein the polyol ispolyethylene glycol, sorbitol, propylene glycol, pentaerythritol or amixture thereof.
 31. The pharmaceutical composition of claim 21, whereinthe hydrophobic surfactant is selected from the group consisting ofmyristic acid; oleic acid; lauric acid; stearic acid; palmitic acid; PEG1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4 dioleate; PEG-4distearate; PEG-6 dioleate; PEG-6 distearate; PEG-8 dioleate; PEG 3-16castor oil; PEG 5-10 hydrogenated castor oil; PEG 6-20 corn oil; PEG6-20 almond oil; PEG-6 olive oil; PEG-6 peanut oil; PEG-6 palm kerneloil; PEG-6 hydrogenated palm kernel oil; PEG-4 capric/caprylictriglyceride, mono, di, tri, tetra esters of vegetable oil and sorbitol;pentaerythrityl di, tetra stearate, isostearate, oleate, caprylate, orcaprate; polyglyceryl 2-4 oleate, stearate, or isostearate; polyglyceryl4-10 pentaoleate; polyglyceryl-3 dioleate; polyglyceryl-6 dioleate;polyglyceryl-10 trioleate; polyglyceryl-3 distearate; propylene glycolmono- or diesters of a C₆ to C₂₀ fatty acid; monoglycerides of a C₆ toC₂₀ fatty acid; acetylated monoglycerides of C₆ to C₂₀ fatty acid;diglycerides of C₆ to C₂₀ fatty acids; lactic acid derivatives ofmonoglycerides; lactic acid derivatives of diglycerides; cholesterol;phytosterol; PEG 5-20 soya sterol; PEG-6 sorbitan tetra, hexastearate;PEG-6 sorbitan tetraoleate; sorbitan monolaurate; sorbitanmonopalmitate; sorbitan mono, trioleate; sorbitan mono, tristearate;sorbitan monoisostearate; sorbitan sesquioleate; sorbitansesquistearate; PEG 2-5 oleyl ether; POE 2-4 lauryl ether; PEG-2 cetylether; PEG-2 stearyl ether; sucrose distearate; sucrose dipalmitate;ethyl oleate; isopropyl myristate; isopropyl palmitate; ethyl linoleate;isopropyl linoleate; poloxamers; and mixtures thereof.
 32. Thepharmaceutical composition of claim 21, wherein the hydrophobicsurfactant is selected from the group consisting of oleic acid; lauricacid; glyceryl monocaprate; glyceryl monocaprylate; glycerylmonolaurate; glyceryl monooleate; glyceryl dicaprate; glyceryldicaprylate; glyceryl dilaurate; glyceryl dioleate; acetylatedmonoglycerides; propylene glycol oleate; propylene glycol laurate;polyglyceryl-3 oleate; polyglyceryl-6 dioleate; PEG-6 corn oil; PEG-20corn oil; PEG-20 almond oil; sorbitan monooleate; sorbitan monolaurate;POE-4 lauryl ether; POE-3 oleyl ether; ethyl oleate; poloxamers; andmixtures thereof.
 33. The pharmaceutical composition of claim 1, whereinthe clear aqueous dispersion has a particle size distribution having anaverage particle size of less than about 100 nm.
 34. The pharmaceuticalcomposition of claim 33, wherein the clear aqueous dispersion has aparticle size distribution having an average particle size of less thanabout 50 nm.
 35. The pharmaceutical composition of claim 33, wherein theclear aqueous dispersion has a particle size distribution having anaverage particle size of less than about 20 nm.
 36. The pharmaceuticalcomposition of claim 1, wherein the clear aqueous dispersion has anabsorbance of less than about 0.1 at about 400 nm when the carrier isdiluted with an aqueous solution in an aqueous solution to carrier ratioof 100:1 by weight.
 37. The pharmaceutical composition of claim 36,wherein the absorbance is less than about 0.01.
 38. The pharmaceuticalcomposition of claim 1, wherein the hydrophobic therapeutic agent has anintrinsic water solubility of less than about 1% by weight at 25° C. 39.The pharmaceutical composition of claim 38, wherein the intrinsic watersolubility is less than about 0.1% by weight at 25° C.
 40. Thepharmaceutical composition of claim 39, wherein the intrinsic watersolubility is less than about 0.01% by weight at 25° C.
 41. Thepharmaceutical composition of claim 1, wherein the therapeutic agent isa drug, a vitamin, a nutritional supplement, a cosmeceutical, or amixture thereof.
 42. The pharmaceutical composition of claim 43, whereinthe therapeutic agent is a polyfunctional hydrophobic drug, a lipophilicdrug, a pharmaceutically acceptable salt, isomer or derivative thereof,or a mixture thereof.
 43. The pharmaceutical composition of claim 41,wherein the therapeutic agent is selected from the group consisting ofanalgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmicagents, anti-bacterial agents, anti-viral agents, anti-coagulants,anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents,anti-gout agents, anti-hypertensive agents, anti-malarials,anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents,erectile dysfunction improvement agents, immunosuppressants,anti-protozoal agents, anti-thyroid agents, anxiolytic agents,sedatives, hypnotics, neuroleptics, β-Blockers, cardiac inotropicagents, corticosteroids, diuretics, anti-parkinsonian agents,gastro-intestinal agents, histamine H,-receptor antagonists,keratolytics, lipid regulating agents, anti-anginal agents, nutritionalagents, opioid analgesics, sex hormones, stimulants, muscle relaxants,anti-osteoporosis agents, anti-obesity agents, cognition enhancers,anti-urinary incontinence agents, nutritional oils, anti-benign prostatehypertrophy agents, essential fatty acids, non-essential fatty acids,and mixtures thereof.
 44. The pharmaceutical composition of claim 41,wherein the therapeutic agent is tramadol, celecoxib, etodolac,refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen,flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole,ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast,azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine,rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir,efavirenz, dicoumarol, tirofibran, cilostazol, ticlidopine, clopidrogel,oprevelkin, paroxetine, sertraline, venlafaxine, bupropion,clomipramine, miglitol, repaglinide, glymepride, pioglitazone,rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide,carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine,vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole,flucanazole, miconazole, ketoconazole, metronidazole, griseofulvin,nitrofurantoin, spironolactone, lisinopril, benezepril, nifedipine,nilsolidipine, telmisartan, irbesartan, eposartan, valsartan,candesartan, minoxidil, terzosin, halofantrine, mefloquine,dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan,zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan,cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide,paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan,nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone,metronidazole, furazolidone, paricalcitol, benzonatate, midazolam,zolpidem, gabapentin, zopiclone, digoxin, beclomethsone, budesonide,betamethasone, prednisolone, cisapride, cimetidine, loperamide,famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole,citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine,fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene,calcitriol, targretin, ergocalciferol, cholecalciferol, isotreinoin,tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil,cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin,tizanidine, dantrolene, isosorbide dinatrate, a carotene,dihydrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, anessential fatty acid source, codeine, fentanyl, methadone, nalbuphine,pentazocine, clomiphene, danazol, dihydro epiandrosterone,medroxyprogesterone, progesterone, rimexolone, megesterol acetate,osteradiol, finasteride, mefepristone, amphetamine, L-thryroxine,tamsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfin,sibutramine, pyridostigmine, a pharmaceutically acceptable salt, isomer,or derivative thereof, or a mixture thereof.
 45. The pharmaceuticalcomposition of claim 1, wherein the hydrophobic therapeutic agent isselected from the group consisting of tramadol, celecoxib, etodolac,refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen,flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole,ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast,azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine,rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir,efavirenz, miglitol, repaglinide, glymepride, pioglitazone,rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide,carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine,vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole,flucanazole, miconazole, ketoconazole, metronidazole, griseofulvin,nitrofurantoin, spironolactone, halofantrine, mefloquine,dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan,zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan,cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide,paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan,nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone,metronidazole, furzolidone, paricalcitol, benzonatate, midazolam,zolpidem, gabapentin, zopiclone, digoxin, cisapride, cimetidine,loperamide, famotidine, lanosprazole, rabeprazole, nizatidine,omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine,clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene,calciprotiene, calcitriol, targretin, ergocalciferol, cholecaliferol,isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil,cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin,tizanidine, dantrolene, carotenes, dihyrotachysterol, vitamin A, vitaminD, vitamin E, vitamin K, essential fatty acid sources, codeine,fentanyl, methdone, nalbuphine, pentazocine, clomiphene, danazol,dihydro epiandrosterone, mmedroxyprogesterone, progesterone, rimexolone,megesterol acetate, osteradiol, finasteride, mefepristone, amphetamine,L-thryroxine, tamsulosin, methoxsalen, tacrine, donepezil, raloxifene,vertoporfin, sibutramine, pyridostigmine, pharmaceutically acceptablesalts, isomers and derivatives thereof, and mixtures thereof.
 46. Thepharmaceutical composition of claim 1, wherein the therapeutic agent isselected from the group consisting of tramadol, celecoxib, etodolac,refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen,flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, ivermectin,amiodarone, zileuton, zafirlukast, albuterol, montelukast, rifabutine,rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir,efavirenz, miglitol, repaglinide, glymepride, pioglitazone,rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide,carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine,vigabatrin, terbenafine, itraconazole, flucanazole, miconazole,ketoconazole, metronidazole, nitrofurantoin, dihydroergotamine,ergotamine, frovatriptan, pizofetin, zolmitriptan, pseudo-ephedrine,naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine,mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus,sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide,toremifene, atovaquone, metronidazole, furzolidone, paricalcitol,benzonatate, cisapride, cimetidine, loperamide, famotidine,lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine,cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine,chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol,targretin, ergocalciferol, cholecaliferol, isotreinoin, tretinoin,calcifediol, fenofibrate, probucol, simvastatin, atorvastatin,tizanidine, dantrolene, carotenes, dihyrotachysterol, vitamin A, vitaminD, vitamin E, vitamin K, essential fatty acid sources, danazol, dihydroepiandrosterone, medroxyprogesterone, progesterone, rimexolone,megesterol acetate, osteradiol, finasteride, mefepristone, raloxifene,L-thryroxine, tamsulosin, methoxsalen, pharmaceutically acceptablesalts, isomers and derivative thereof, and mixtures thereof.
 47. Thepharmaceutical composition of claim 1, wherein the hydrophobictherapeutic agent is selected from the group consisting of sildenafilcitrate, amlodipine, tramadol, celecoxib, refocoxib, oxaprozin,nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast,cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine,loratadine, famotidine, paricalcitol, atovaquone, nabumetone,tetrahydrocannabinol, megesterol acetate, repaglinide, progesterone,rimexolone, cyclosporine, tacrolimus, sirolimus, teniposide, paclitaxel,pseudo-ephedrine, troglitazone, rosiglitazone, finasteride, vitamin A,vitamin D, vitamin E, pharmaceutically acceptable salts, isomers andderivatives thereof, and mixtures thereof.
 48. The pharmaceuticalcomposition of claim 1, wherein the hydrophobic therapeutic agent isprogesterone or cyclosporin.
 49. The pharmaceutical composition of claim1, which further comprises a solubilizer.
 50. The pharmaceuticalcomposition of claim 49, wherein the solubilizer is selected from thegroup consisting of alcohols, polyols, amides, esters, propylene glycolethers and mixtures thereof.
 51. The pharmaceutical composition of claim50, wherein the alcohol or polyol is selected from the group consistingof ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol,propylene glycol, butanediols and isomers thereof, glycerol,pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide,polyethylene glycol, polypropylene glycol, polyvinylalcohol,hydroxypropyl methylcellulose and other cellulose derivatives,cyclodextrins and cyclodextrin derivatives, and mixtures thereof. 52.The pharmaceutical composition of claim 50, wherein the amide isselected from the group consisting of 2-pyrrolidone, 2-piperidone,ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone,N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide,polyvinylpyrrolidone, and mixtures thereof.
 53. The pharmaceuticalcomposition of claim 50, wherein the ester is selected from the groupconsisting of ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof, and mixturesthereof.
 54. The pharmaceutical composition of claim 49, wherein thesolubilizer is selected from the group consisting of ethanol,isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol,butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol,mannitol, transcutol, dimethyl isosorbide, polyethylene glycol,polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcelluloseand other cellulose derivatives, cyclodextrins, clodextrins andderivatives thereof, ethyl propionate, tributylcitrate, acetyltriethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate,ethyl caprylate, ethyl butyrate, triacetin, propylene glycol diacetate,ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof,β-butyrolactone and isomers thereof, 2-pyrrolidone, 2-2 piperidone,ε-caprolactam, N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethylpyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide,polyvinylpyrrolidone, glycofurol, methoxy PEG, and mixtures thereof. 55.The pharmaceutical composition of claim 49, wherein the solubilizer isselected from the group consisting of ethanol, isopropanol, benzylalcohol, ethylene glycol, propylene glycol, 1,3-butanediol, glycerol,pentaerythritol, sorbitol, glycofurol, transcutol, dimethyl isosorbide,polyethylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose,methylcellulose, ethylcellulose, hydroxypropylcyclodextrins, sulfobutylether derivatives of cyclodextrins, ethyl propionate, tributylcitrate,triethylcitrate, ethyl oleate, ethyl caprylate, triacetin,β-butyrolactone and isomers thereof, 2-pyrrolidone, N-methylpyrrolidone,N-ethylpyrrolidone, N-hydroxyethylpyrrolidone, N-octylpyrrolidone,N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, andmixtures thereof.
 56. The pharmaceutical composition of claim 49,wherein the solubilizer is triacetin, triethylcitrate, ethyl oleate,ethyl caprylate, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethyleneglycol 200-600, glycofurol, transcutol, propylene glycol, dimethylisosorbide, or a mixture thereof.
 57. The pharmaceutical composition ofclaim 49, wherein the solubilizer is triacetin, ethanol, polyethyleneglycol 400, glycofurol, propylene glycol or a mixture thereof.
 58. Thepharmaceutical composition of claim 49, wherein the solubilizer ispresent in the composition in an amount of about 400% or less by weight,based on the total weight of the surfactants.
 59. The pharmaceuticalcomposition of claim 58, wherein the solubilizer is present in thecomposition in an amount of about 200% or less by weight, based on thetotal weight of the surfactants.
 60. The pharmaceutical composition ofclaim 59, wherein the solubilizer is present in the composition in anamount of about 100% or less by weight, based on the total weight of thesurfactants.
 62. The pharmaceutical composition of claim 60, wherein thesolubilizer is present in the composition in an amount of about 50% orless by weight, based on the total weight of the surfactants.
 62. Thepharmaceutical composition of claim 61, wherein the solubilizer ispresent in the composition in an amount about 25% or less by weight,based on the total weight of the surfactants.
 63. The pharmaceuticalcomposition of claim 1, which further comprises an antioxidant, apreservative, a chelating agent, a viscomodulator, a tonicifier, aflavorant, a colorant, an odorant, an opacifier, a suspending agent, abinder, or a mixture thereof.
 64. The pharmaceutical composition ofclaim 1 in the form of a preconcentrate, a diluted preconcentrate, asemi-solid dispersion, a solid dispersion, or a sprayable solution. 65.A dosage form comprising a capsule filled with the pharmaceuticalcomposition of claim
 1. 66. A dosage form comprising a multiparticulatecarrier coated with the pharmaceutical composition of claim
 1. 67. Adosage form comprising the pharmaceutical composition of claim 1formulated as a solution, a cream, a lotion, an ointment, a suppository,a spray, an aerosol, a paste or a gel.
 68. The dosage form of claim 65,wherein the capsule is a hard gelatin capsule, a soft gelatin capsule, astarch capsule or an enteric coated capsule.
 69. The pharmaceuticalcomposition of claim 1, which further comprises water or an aqueousbuffer.
 70. The pharmaceutical composition of claim 1, which furthercomprises an additional amount of a hydrophobic therapeutic agent, saidadditional amount not solubilized in the carrier.
 71. A pharmaceuticalcomposition comprising: (a) at least one hydrophilic surfactant; (b) atleast one hydrophobic surfactant; and (c) a hydrophobic therapeuticagent, said pharmaceutical composition being in the form of a clear,aqueous dispersion which is substantially free of triglycerides.
 72. Thepharmaceutical composition of claim 71, wherein the hydrophobicsurfactant is present in an amount of less than about 200% by weight,relative to the amount of the hydrophilic surfactant.
 73. Thepharmaceutical composition of claim 72, wherein the hydrophobicsurfactant is present in an amount of less than about 100% by weight,relative to the amount of the hydrophilic surfactant.
 74. Thepharmaceutical composition of claim 73, wherein the hydrophobicsurfactant is present in an amount of less than about 60% by weight,relative to the amount of the hydrophilic surfactant.
 75. Thepharmaceutical composition of claim 71, wherein the hydrophilicsurfactant comprises at least one non-ionic hydrophilic surfactanthaving an HLB value greater than or equal to about
 10. 76. Thepharmaceutical composition of claim 71, wherein the hydrophilicsurfactant comprises at least one ionic surfactant.
 77. Thepharmaceutical composition of claim 75, which further comprises at leastone ionic surfactant.
 78. The pharmaceutical composition of claim 75,wherein the non-ionic surfactant is selected from the group consistingof alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyethylene alkylethers; polyoxyethylenealkylphenols; polyethylene glycol fatty acids esters; polyethyleneglycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acidesters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerolfatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction mixtures ofpolyols and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;sugar esters, sugar ethers; sucroglycerides; and mixtures thereof. 79.The pharmaceutical composition of claim 75, wherein the non-ionichydrophilic surfactant is selected from the group consisting ofpolyoxyethylene alkylethers; polyethylene glycol fatty acids esters;polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitanfatty acid esters; polyoxyethylene-polyoxypropylene block copolymers;polyglycerol fatty acid esters; polyoxyethylene glycerides;polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetableoils; reaction mixtures of polyols and at least one member of the groupconsisting of fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols; and mixtures thereof.
 80. Thepharmaceutical composition of claim 79, wherein the glyceride is amonoglyceride, diglyceride, triglyceride, or a mixture thereof.
 81. Thepharmaceutical composition of claim 79, wherein the reaction mixturecomprises the transesterification products of a polyol and at least onemember of the group consisting of fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols.
 82. The pharmaceuticalcomposition of claim 79, wherein the polyol is glycerol, ethyleneglycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritolor a mixture thereof.
 83. The pharmaceutical composition of claim 75,wherein the hydrophilic surfactant is PEG-10 laurate, PEG-12 laurate,PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate,PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate,PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate,PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kerneloil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castoroil, PEG-60 castor oil, PEG40 hydrogenated castor oil, PEG-60hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylateglycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate,PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherylPEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40,Tween 60, sucrose monostearate, sucrose monolaurate, sucrosemonopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenolseries, a poloxamer, or a mixture thereof.
 84. The pharmaceuticalcomposition of claim 75, wherein the hydrophilic surfactant is PEG-20laurate, PEG-20 oleate, PEG-35 castor oil, PEG-40 palm kernel oil,PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryltrioleate, polyglyceryl-10 laurate, PEG-6 caprate/caprylate glycerides,PEG-8 caprate/caprylate glycerides, PEG-30 cholesterol, polysorbate 20,polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleylether, PEG-24 cholesterol, sucrose monostearate, sucrose monolaurate, apoloxamer, or a mixture thereof.
 85. The pharmaceutical composition ofclaim 75, wherein the hydrophilic surfactant is PEG-35 castor oil, PEG40hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate,PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polysorbate 20, polysorbate 80, tocopheryl PEG-1000 succinate, PEG-24cholesterol, a poloxamer, or a mixture thereof.
 86. The pharmaceuticalcomposition of claim 76, wherein the ionic surfactant is selected fromthe group consisting of alkyl ammonium salts; bile acids and salts,analogues, and derivatives thereof; fatty acid derivatives of aminoacids, oligopeptides, and polypeptides; glyceride derivatives of aminoacids, oligopeptides, and polypeptides; acyl lactylates;mono-,diacetylated tartaric acid esters of mono-,diglycerides;succinylated monoglycerides; citric acid esters of mono-,diglycerides;alginate salts; propylene glycol alginate; lecithins and hydrogenatedlecithins; lysolecithin and hydrogenated lysolecithins;lysophospholipids and derivatives thereof; phospholipids and derivativesthereof; salts of alkylsulfates; salts of fatty acids; sodium docusate;and mixtures thereof.
 87. The pharmaceutical composition of claim 76,wherein the ionic surfactant is selected from the group consisting ofbile acids and salts, analogues, and derivatives thereof; lecithins,lysolecithin, phospholipids, lysophospholipids and derivatives thereof;salts of alkylsulfates; salts of fatty acids; sodium docusate; acyllactylates; mono-,diacetylated tartaric acid esters ofmono-,diglycerides; succinylated monoglycerides; citric acid esters ofmono-,diglycerides; and mixtures thereof.
 88. The pharmaceuticalcomposition of claim 76, wherein the ionic surfactant is selected fromthe group consisting of lecithin, lysolecithin, phosphatidylcholine,phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid,phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholate, taurocholate, glycocholate,deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate,glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate,tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyltaurocholate, caproate, caprylate, caprate, laurate, myristate,palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, laurylsulfate, teracecyl sulfate, docusate, and salts and mixtures thereof.89. The pharmaceutical composition of claim 76, wherein the ionicsurfactant is selected from the group consisting of lecithin,lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylglycerol, lysophosphatidylcholine,PEG-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholate, taurocholate, glycocholate,deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine,caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate,and salts and mixtures thereof.
 90. The pharmaceutical composition ofclaim 76, wherein the ionic surfactant is selected from the groupconsisting of lecithin, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, taurocholate, caprylate, caprate, oleate,lauryl sulfate, docusate, and salts and mixtures thereof.
 91. Thepharmaceutical composition of claim 71 wherein the hydrophobicsurfactant is a compound or mixture of compounds having an HLB valueless than about
 10. 92. The pharmaceutical composition of claim 91,wherein the hydrophobic surfactant is selected from the group consistingof alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fattyacid esters; acetylated glycerol fatty acid esters; lower alcohol fattyacids esters; polyethylene glycol fatty acids esters; polyethyleneglycol glycerol fatty acid esters; polypropylene glycol fatty acidesters; polyoxyethylene glycerides; lactic acid derivatives ofmono/diglycerides; propylene glycol diglycerides; sorbitan fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; transesterifiedvegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers;sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylenehydrogenated vegetable oils; reaction mixtures of polyols and at leastone member of the group consisting of fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols; and mixtures thereof.93. The pharmaceutical composition of claim 91, wherein the hydrophobicsurfactant is selected from the group consisting of fatty acids; loweralcohol fatty acid esters; polyethylene glycol glycerol fatty acidesters; polypropylene glycol fatty acid esters; polyoxyethyleneglycerides; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lactic acid derivatives of mono/diglycerides; sorbitan fattyacid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylenevegetable oils; polyoxyethylene hydrogenated vegetable oils; reactionmixtures of polyols and at least one member of the group consisting offatty acids, glycerides, vegetable oils, hydrogenated vegetable oils,and sterols; and mixtures thereof.
 94. The pharmaceutical composition ofclaim 91, wherein the hydrophobic surfactant is selected from the groupconsisting of lower alcohol fatty acids esters; polypropylene glycolfatty acid esters; propylene glycol fatty acid esters; glycerol fattyacid esters; acetylated glycerol fatty acid esters; lactic acidderivatives of mono/diglycerides; sorbitan fatty acid esters;polyoxyethylene vegetable oils; and mixtures thereof.
 95. Thepharmaceutical composition of claim 91, wherein the hydrophobicsurfactant is a glycerol fatty acid ester, an acetylated glycerol fattyacid ester, or a mixture thereof.
 96. The pharmaceutical composition ofclaim 95, wherein the glycerol fatty acid ester is a monoglyceride,diglyceride, or a mixture thereof.
 97. The pharmaceutical composition ofclaim 96, wherein the fatty acid of the glycerol fatty acid ester is aC₆ to C₂₀ fatty acid or a mixture thereof.
 98. The pharmaceuticalcomposition of claim 91, wherein the hydrophobic surfactant is areaction mixture of a polyol and at least one member of the groupconsisting of fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols.
 99. The pharmaceutical composition of claim98, wherein the reaction mixture is a transesterification product of apolyol and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.100. The pharmaceutical composition of claim 98, wherein the polyol ispolyethylene glycol, sorbitol, propylene glycol, pentaerythritol or amixture thereof.
 101. The pharmaceutical composition of claim 91,wherein the hydrophobic surfactant is selected from the group consistingof myristic acid; oleic acid; lauric acid; stearic acid; palmitic acid;PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4 dioleate; PEG-4distearate; PEG-6 dioleate; PEG-6 distearate; PEG-8 dioleate; PEG 3-16castor oil; PEG 5-10 hydrogenated castor oil; PEG 6-20 corn oil; PEG6-20 almond oil; PEG-6 olive oil; PEG-6 peanut oil; PEG-6 palm kerneloil; PEG-6 hydrogenated palm kernel oil; PEG-4 capric/caprylictriglyceride, mono, di, tri, tetra esters of vegetable oil and sorbitol;pentaerythrityl di, tetra stearate, isostearate, oleate, caprylate, orcaprate; polyglyceryl 2-4 oleate, stearate, or isostearate; polyglyceryl4-10 pentaoleate; polyglyceryl-3 dioleate; polyglyceryl-6 dioleate;polyglyceryl-10 trioleate; polyglyceryl-3 distearate; propylene glycolmono- or diesters of a C₆ to C₂₀ fatty acid; monoglycerides of a C₆ toC₂₀ fatty acid; acetylated monoglycerides of C₆ to C₂₀ fatty acid;diglycerides of C₆ to C₂₀ fatty acids; lactic acid derivatives ofmonoglycerides; lactic acid derivatives of diglycerides; cholesterol;phytosterol; PEG 5-20 soya sterol; PEG-6 sorbitan tetra, hexastearate;PEG-6 sorbitan tetraoleate; sorbitan monolaurate; sorbitanmonopalmitate; sorbitan mono, trioleate; sorbitan mono, tristearate;sorbitan monoisostearate; sorbitan sesquioleate; sorbitansesquistearate; PEG 2-5 oleyl ether; POE 2-4 lauryl ether; PEG-2 cetylether; PEG-2 stearyl ether; sucrose distearate; sucrose dipalmitate;ethyl oleate; isopropyl myristate; isopropyl palmitate; ethyl linoleate;isopropyl linoleate; poloxamers; and mixtures thereof.
 102. Thepharmaceutical composition of claim 91, wherein the hydrophobicsurfactant is selected from the group consisting of oleic acid; lauricacid; glyceryl monocaprate; glyceryl monocaprylate; glycerylmonolaurate; glyceryl monooleate; glyceryl dicaprate; glyceryldicaprylate; glyceryl dilaurate; glyceryl dioleate; acetylatedmonoglycerides; propylene glycol oleate; propylene glycol laurate;polyglyceryl-3 oleate; polyglyceryl-6 dioleate; PEG-6 corn oil; PEG-20corn oil; PEG-20 almond oil; sorbitan monooleate; sorbitan monolaurate;POE-4 lauryl ether; POE-3 oleyl ether; ethyl oleate; poloxamers; andmixtures thereof.
 103. The pharmaceutical composition of claim 71,wherein the clear aqueous dispersion has a particle size distributionhaving an average particle size of less than about 100 nm.
 104. Thepharmaceutical composition of claim 103, wherein the clear aqueousdispersion has a particle size distribution having an average particlesize of less than about 50 nm.
 105. The pharmaceutical composition ofclaim 103, wherein the clear aqueous dispersion has a particle sizedistribution having an average particle size of less than about 20 nm.106. The pharmaceutical composition of claim 71, wherein the clearaqueous dispersion has an absorbance of less than about 0.1 at 400 nmwhen the ratio of the weight of water to the total weight of thehydrophilic surfactant, the hydrophobic surfactant and the therapeuticagent is 100:1.
 107. The pharmaceutical composition of claim 106,wherein the absorbance is less than about 0.01.
 108. The pharmaceuticalcomposition of claim 71, wherein the hydrophobic therapeutic agent hasan intrinsic water solubility of less than about 1% by weight at 25° C.109. The pharmaceutical composition of claim 108, wherein the intrinsicwater solubility is less than about 0.1% by weight at 25° C.
 110. Thepharmaceutical composition of claim 109, wherein the intrinsic watersolubility is less than about 0.01% by weight at 25° C.
 111. Thepharmaceutical composition of claim 71, wherein the therapeutic agent isa drug, a vitamin, a nutritional supplement, a cosmeceutical, or amixture thereof.
 112. The pharmaceutical composition of claim 111,wherein the therapeutic agent is a polyfunctional hydrophobic drug, alipophilic drug, a pharmaceutically acceptable salt, isomer orderivative thereof, or a mixture thereof.
 113. The pharmaceuticalcomposition of claim 111, wherein the therapeutic agent is selected fromthe group consisting of analgesics, anti-inflammatory agents,anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viralagents, anti-coagulants, anti-depressants, anti-diabetics,anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensiveagents, anti-malarials, anti-migraine agents, anti-muscarinic agents,anti-neoplastic agents, erectile dysfunction improvement agents,immunosuppressants, anti-protozoal agents, anti-thyroid agents,anxiolytic agents, sedatives, hypnotics, neuroleptics, β-Blockers,cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonianagents, gastro-intestinal agents, histamine H,-receptor antagonists,keratolytics, lipid regulating agents, anti-anginal agents, nutritionalagents, opioid analgesics, sex hormones, stimulants, muscle relaxants,anti-osteoporosis agents, anti-obesity agents, cognition enhancers,anti-urinary incontinence agents, nutritional oils, anti-benign prostatehypertrophy agents, essential fatty acids, non-essential fatty acids,and mixtures thereof.
 114. The pharmaceutical composition of claim 111,wherein the therapeutic agent is tramadol, celecoxib, etodolac,refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen,flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole,ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast,azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine,rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir,efavirenz, dicoumarol, tirofibran, cilostazol, ticlidopine, clopidrogel,oprevelkin, paroxetine, sertraline, venlafaxine, bupropion,clomipramine, miglitol, repaglinide, glymepride, pioglitazone,rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide,carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine,vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole,flucanazole, miconazole, ketoconazole, metronidazole, griseofulvin,nitrofurantoin, spironolactone, lisinopril, benezepril, nifedipine,nilsolidipine, telmisartan, irbesartan, eposartan, valsartan,candesartan, minoxidil, terzosin, halofantrine, mefloquine,dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan,zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan,cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide,paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan,nilutanide, bicalutanide, ephedrine, toremifene, atovaquone,metronidazole, furazolidone, paricalcitol, benzonatate, midazolam,zolpidem, gabapentin, zopiclone, digoxin, beclomethsone, budesonide,betamethasone, prednisolone, cisapride, cimetidine, loperamide,famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole,citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine,fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene,calcitriol, targretin, ergocalciferol, cholecalciferol, isotreinoin,tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil,cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin,tizanidine, dantrolene, isosorbide dinatrate, a carotene,dihydrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, anessential fatty acid source, codeine, fentanyl, methadone, nalbuphine,pentazocine, clomiphene, danazol, dihydro epiandrosterone,medroxyprogesterone, progesterone, rimexolone, megesterol acetate,osteradiol, finasteride, mefepristone, amphetamine, L-thryroxine,tamsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfin,sibutramine, pyridostigmine, a pharmaceutically acceptable salt, isomer,or derivative thereof, or a mixture thereof.
 115. The pharmaceuticalcomposition of claim 71, wherein the hydrophobic therapeutic agent isselected from the group consisting of tramadol, celecoxib, etodolac,refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen,flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole,ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast,azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine,rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir,efavirenz, miglitol, repaglinide, glymepride, pioglitazone,rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide,carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine,vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole,flucanazole, miconazole, ketoconazole, metronidazole, griseofulvin,nitrofurantoin, spironolactone, halofantrine, mefloquine,dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan,zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan,cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide,paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan,nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone,metronidazole, furzolidone, paricalcitol, benzonatate, midazolam,zolpidem, gabapentin, zopiclone, digoxin, cisapride, cimetidine,loperamide, famotidine, lanosprazole, rabeprazole, nizatidine,omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine,clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene,calciprotiene, calcitriol, targretin, ergocalciferol, cholecaliferol,isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil,cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin,tizanidine, dantrolene, carotenes, dihyrotachysterol, vitamin A, vitaminD, vitamin E, vitamin K, essential fatty acid sources, codeine,fentanyl, methdone, nalbuphine, pentazocine, clomiphene, danazol,dihydro epiandrosterone, mmedroxyprogesterone, progesterone, rimexolone,megesterol acetate, osteradiol, finasteride, mefepristone, amphetamine,L-thryroxine, tamsulosin, methoxsalen, tacrine, donepezil, raloxifene,vertoporfin, sibutramine, pyridostigmine, pharmaceutically acceptablesalts, isomers and derivatives thereof, and mixtures thereof.
 116. Thepharmaceutical composition of claim 71, wherein the therapeutic agent isselected from the group consisting of tramadol, celecoxib, etodolac,refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen,flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, ivermectin,amiodarone, zileuton, zafirlukast, albuterol, montelukast, rifabutine,rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir,efavirenz, miglitol, repaglinide, glymepride, pioglitazone,rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide,carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine,vigabatrin, terbenafine, itraconazole, flucanazole, miconazole,ketoconazole, metronidazole, nitrofurantoin, dihydroergotamine,ergotamine, frovatriptan, pizofetin, zolmitriptan, pseudo-ephedrine,naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine,mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus,sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide,toremifene, atovaquone, metronidazole, furzolidone, paricalcitol,benzonatate, cisapride, cimetidine, loperamide, famotidine,lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine,cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine,chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol,targretin, ergocalciferol, cholecaliferol, isotreinoin, tretinoin,calcifediol, fenofibrate, probucol, simvastatin, atorvastatin,tizanidine, dantrolene, carotenes, dihyrotachysterol, vitamin A, vitaminD, vitamin E, vitamin K, essential fatty acid sources, danazol, dihydroepiandrosterone, medroxyprogesterone, progesterone, rimexolone,megesterol acetate, osteradiol, finasteride, mefepristone, raloxifene,L-thryroxine, tamsulosin, methoxsalen, pharmaceutically acceptablesalts, isomers and derivative thereof, and mixtures thereof.
 117. Thepharmaceutical composition of claim 71, wherein the hydrophobictherapeutic agent is selected from the group consisting of sildenafilcitrate, amlodipine, tramadol, celecoxib, refocoxib, oxaprozin,nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast,cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine,loratadine, famotidine, paricalcitol, atovaquone, nabumetone,tetrahydrocannabinol, megesterol acetate, repaglinide, progesterone,rimexolone, cyclosporine, tacrolimus, sirolimus, teniposide, paclitaxel,pseudo-ephedrine, troglitazone, rosiglitazone, finasteride, vitamin A,vitamin D, vitamin E, pharmaceutically acceptable salts, isomers andderivatives thereof, and mixtures thereof.
 118. The pharmaceuticalcomposition of claim 71, wherein the hydrophobic therapeutic agent isprogesterone or cyclosporin.
 119. The pharmaceutical composition ofclaim 71, which further comprises a solubilizer.
 120. The pharmaceuticalcomposition of claim 119, wherein the solubilizer is selected from thegroup consisting of alcohols, polyols, amides, esters, polyethyleneglycol ethers and mixtures thereof.
 121. The pharmaceutical compositionof claim 120, wherein the alcohol or polyol is selected from the groupconsisting of ethanol, isopropanol, butanol, benzyl alcohol, ethyleneglycol, propylene glycol, butanediols and isomers thereof, glycerol,pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide,polyethylene glycol, polypropylene glycol, polyvinylalcohol,hydroxypropyl methylcellulose and other cellulose derivatives,cyclodextrins and cyclodextrin derivatives, and mixtures thereof. 122.The pharmaceutical composition of claim 120, wherein the amide isselected from the group consisting of 2-pyrrolidone, 2-piperidone,ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone,N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide,polyvinylpyrrolidone, and mixtures thereof.
 123. The pharmaceuticalcomposition of claim 120, wherein the ester is selected from the groupconsisting of ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof, and mixturesthereof.
 124. The pharmaceutical composition of claim 119, wherein thesolubilizer is selected from the group consisting of ethanol,isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol,butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol,mannitol, transcutol, dimethyl isosorbide, polyethylene glycol,polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcelluloseand other cellulose derivatives, cyclodextrins, clodextrins andderivatives thereof, ethyl propionate, tributylcitrate, acetyltriethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate,ethyl caprylate, ethyl butyrate, triacetin, propylene glycol diacetate,ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof,β-butyrolactone and isomers thereof, 2-pyrrolidone, 2-piperidone,ε-caprolactam, N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethylpyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide,polyvinylpyrrolidone, glycofurol, methoxy PEG, and mixtures thereof.125. The pharmaceutical composition of claim 119, wherein thesolubilizer is selected from the group consisting of ethanol,isopropanol, benzyl alcohol, ethylene glycol, propylene glycol,1,3-butanediol, glycerol, pentaerythritol, sorbitol, glycofurol,transcutol, dimethyl isosorbide, polyethylene glycol, polyvinylalcohol,hydroxypropyl methylcellulose, methylcellulose, ethylcellulose,hydroxypropylcyclodextrins, sulfobutyl ether derivatives ofcyclodextrins, ethyl propionate, tributylcitrate, triethylcitrate, ethyloleate, ethyl caprylate, triacetin, β-butyrolactone and isomers thereof,2-pyrrolidone, N-methylpyrrolidone, N-ethylpyrrolidone,N-hydroxyethylpyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone,dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.
 126. Thepharmaceutical composition of claim 119, wherein the solubilizer istriacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol,transcutol, propylene glycol, dimethyl isosorbide, or a mixture thereof.127. The pharmaceutical composition of claim 119, wherein thesolubilizer is triacetin, ethanol, polyethylene glycol 400, glycofurol,propylene glycol or a mixture thereof.
 128. The pharmaceuticalcomposition of claim 119, wherein the solubilizer is present in thecomposition in an amount of about 400% or less by weight, based on thetotal weight of the surfactants.
 129. The pharmaceutical composition ofclaim 128, wherein the solubilizer is present in the composition in anamount of about 200% or less by weight, based on the total weight of thesurfactants.
 130. The pharmaceutical composition of claim 129, whereinthe solubilizer is present in the composition in an amount of about 100%or less by weight, based on the total weight of the surfactants. 131.The pharmaceutical composition of claim 130, wherein the solubilizer ispresent in the composition in an amount of about 50% or less by weight,based on the total weight of the surfactants.
 132. The pharmaceuticalcomposition of claim 131, wherein the solubilizer is present in thecomposition in an amount about 25% or less by weight, based on the totalweight of the surfactants.
 133. The pharmaceutical composition of claim71, which further comprises an antioxidant, a preservative, a chelatingagent, a viscomodulator, a tonicifier, a flavorant, a colorant, anodorant, an opacifier or a mixture thereof.
 134. The pharmaceuticalcomposition of claim 71, which further comprises an additional amount ofa hydrophobic therapeutic agent, said additional amount not solubilizedin the carrier.
 135. A pharmaceutical composition comprising: (a) acarrier,  said carrier comprising: (i) at least one hydrophilicsurfactant; and (ii) at least one hydrophobic surfactant,  saidhydrophilic and hydrophobic surfactants being present in amounts suchthat upon mixing with an aqueous solution the carrier forms a clearaqueous dispersion of the hydrophilic and hydrophobic surfactants; (b) afirst amount of a hydrophobic therapeutic agent, said first amount beingsolubilized in the carrier; and (c) a second amount of a hydrophobictherapeutic agent, said second amount not solubilized in the clearaqueous dispersion, said composition being substantially free oftriglycerides.
 136. A method of treating an animal with a hydrophobictherapeutic agent, the method comprising: providing a dosage form of apharmaceutical composition comprising: a hydrophobic therapeutic agent;and a carrier,  said carrier comprising: at least one hydrophilicsurfactant; and at least one hydrophobic surfactant,  said hydrophilicand hydrophobic surfactants being present in amounts such that uponmixing with an aqueous solution the carrier forms a clear aqueousdispersion of the hydrophilic and hydrophobic surfactants containing thehydrophobic therapeutic agent, said composition being substantially freeof triglycerides; and administering said dosage form to said animal.137. The method of claim 136, wherein the dosage form is a capsule, acream, a lotion, an ointment, a suppository, a paste or a gel.
 138. Themethod of claim 136, wherein the dosage form is administered by an oral,parenteral, topical, transdermal, ocular, pulmonary, vaginal, rectal ortransmucosal route.
 139. The method of claim 136, wherein the animal isa mammal.
 140. The method of claim 139, wherein the mammal is a human.